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Article

Influence of Dipole Orientation of Zwitterionic Materials on Hemodialysis Membrane Interactions with Human Serum Proteins

by
Simin Nazari
1 and
Amira Abdelrasoul
1,2,*
1
Division of Biomedical Engineering, University of Saskatchewan, 57 Campus Drive, Saskatoon, SK S7N 5A9, Canada
2
Department of Chemical and Biological Engineering, University of Saskatchewan, 57 Campus Drive, Saskatoon, SK S7N 5A9, Canada
*
Author to whom correspondence should be addressed.
Appl. Sci. 2023, 13(23), 12777; https://doi.org/10.3390/app132312777
Submission received: 25 September 2023 / Revised: 19 October 2023 / Accepted: 25 October 2023 / Published: 28 November 2023
Browse Figures
Versions Notes

Abstract

:
Hemodialysis is a lifesaving treatment for end-stage renal disease (ESRD) that exploits semipermeable membranes to remove fluids and uremic toxins from ESRD patients. Polyethersulfone (PES) is the most common membrane that is currently used in Canadian hospitals and represents 93% of the market. Nevertheless, PES membranes have limited hemocompatibility, which triggers blood activation cascades, as the rate of morbidity and mortality in ESRD patients is still unacceptably high. Surface modification with zwitterionic (ZW) materials, which are well known for their strong dipole–dipole interactions and exceptional antifouling properties, has recently received increased attention in improving PES characteristics like roughness, wettability, and biocompatibility, which are crucial factors in dialysis efficiency. The hydration structures, dynamics, and interactions of ZWs are significantly dependent on the backbone structures, such as differences in carbon space length [CSL], conformation, functional groups, pendant groups, and charge distributions, and even minor changes in ZW structure can drastically alter their behavior. However, a systematic investigation of the impact of dipole orientation of ZW on the hemocompatibility of the membranes has not yet been investigated. This study offers a comprehensive exploration of the interactions between hemodialysis membranes and human serum proteins, emphasizing the pivotal role of the zwitterion dipole orientation. We utilize molecular docking techniques to predict protein–ligand interactions, offering insights into the binding sites and binding energy of these complexes. The effect of dipole orientation on the hemocompatibility of various ZW-modified PES membranes compared to the pristine PES has been investigated using 2-methacryloyloxyethyl phosphorylcholine (MPC), 2-((2-(methacryloyloxy)ethyl)dimethylammonio)ethyl methyl phosphate (MMP), and butyl (2-((2-(methacryloyloxy)ethyl)dimethylammonio)ethyl) phosphate (MBP) zwitterions with opposite dipole orientations. Results showed that the protein–ligand interactions and affinity energies displayed by the reverse dipole moment structures are remarkably different. It was demonstrated that the MBP–PES ligand had the lowest affinity energy to interact with all examined human serum proteins compared to the structure, which had an opposite dipole moment. As a result, this membrane surface has better antifouling properties and, thus, higher hemocompatibility, which directly correlates with greater efficiency of hemodialysis in patients.

1. Introduction

Hemodialysis (HD), also known as renal replacement therapy (RRT), is a procedure to remove extra fluid and uremic toxins from ESRD patients [1,2]. There is no question that ESRD is a serious public health concern that is inexorably growing. Alongside diabetes and dementia, the mortality rate associated with renal disease has seen a significant increase over the past decade [3,4]. In contrast, during the same period, global mortality rates for noncommunicable diseases such as heart disease and pulmonary conditions have declined [5,6].
Polyether sulfone (PES) is the most common HD membrane used in Canadian hospitals and represents 93% of the market. Nevertheless, PES membranes have limited hemocompatibility, which triggers blood activation cascades, and the rate of morbidity and mortality in ESRD patients is still unacceptably high. Thus, there has been significant interest in developing hemocompatible membranes for blood purification. This focus stems from the need to address the primary challenges associated with intra- and posthemodialysis complications, aiming to enhance hemodialysis efficiency and ensure its efficacy for all patients [7,8,9]. Due to interactions between human serum proteins and HD membranes, the incompatible HD membrane causes unfavorable biological reactions that start complement, leukocyte, and coagulation bioactivation cascades [10]. When the proper membrane type, material, and surface design are not carefully taken into consideration, the majority of these reactions result in total renal failure, diabetes, fatigue, cardiovascular disorders, and even death [11,12,13]. Among different modification techniques, a large number of studies have recently been published in the literature focusing on the zwitterionization of membrane structures to improve their hemocompatibility, which has been intensively studied by our research group [10,14,15,16,17,18].
ZW polymers are the last generation of antifouling materials, which have an electrically neutral overall surface charge despite having distinct cationic and anionic groups on each monomer. Such polymeric backbones with an equal number of positive and negative parts are extremely hydrophilic, stable, and hemocompatible and are also an excellent antifouling material [18,19]. A ZW structure has a large dipole moment and is composed of numerous highly charged groups, which results in exceptional ion conductivity and very strong polarity compared to conventional polymers that do not contain charges [20,21,22,23]. ZW materials have been widely used in anti-biofouling surfaces as the hydration shell around polyzwitterions, which is formed via electrostatic interactions with water molecules that can back away any other biomolecule, including protein chains [24,25]. The zwitterionic chemical structure influences its polarity, hydrophobicity, hemocompatibility, and anti-polyelectrolyte activity. For instance, it was demonstrated that the length of the carbon spacer (CSL), which is the quantity of -CH2 units separating the opposite charge moieties, can have a significant impact on the ZW characteristics. CSL significantly influences the hydrophilic/hydrophobic balance as well as the flexibility of the ZW backbone, thereby altering its optimized conformation and electrostatic interactions [26,27,28,29]. Additionally, the changing pendant groups and functional groups of ZW have a direct impact on ZW properties [30,31,32]. Although various spacer lengths, heads, and other factors have been intensively explored by researchers, none of them have studied the effect of dipole orientation on ZW interactions with human serum proteins and its hemocompatibility, which is one of the most important characteristics of ZWs [33,34].
The study of protein–ligand interactions as the hemocompatibility indicator is becoming more and more important due to its key role and potential applications in biotechnology and medicine. Computational docking is useful modeling for predicting bound conformations and binding free energies for small-molecule ligands to macromolecular targets instead of time- and energy-consuming experimental research. Our group has studied the interaction of human blood proteins with membrane models using molecular docking [10,16,17,35,36]. Those studies were crucial to providing insights and highlighting the functional group(s) that are responsible for the interactions with human serum proteins. Based on the computational results, our research group has developed novel ZW membranes that reduce the inflammatory biomarkers released in dialysis patients’ serum [33,34,35]. Furthermore, our research group has recently conducted in-depth molecular docking studies on biocompatible Trametes versicolor and versicolor and melanocarpusalbomyces laccases to remove protein-bound uremic toxins (PBUT) [37].
This study sought to explore the influence of the dipole orientation of the ZW chain on the interactions between the PES membrane and essential human serum proteins, with the goal of enhancing PES hemocompatibility. While the zwitterionization of membranes is a well-documented method for improving hemocompatibility, and the dipole moment is a crucial attribute of zwitterions, our research marks the first systematic examination of how the dipole orientation of ZW impacts membrane hemocompatibility. The objectives of the study were as follows: (i) study the ligand–protein interactions between two opposite dipole orientation zwitterionic structures and three vital human serum proteins, Fibrinogen (FB), Albumin (HSA), and Transferrin (Tr), using molecular docking; (ii) investigate the influence of the ZW dipole orientation on its interactions with the three different human serum proteins; (iii) identify the functional groups responsible for perceived interactions between 2-methacryloyloxyethyl phosphorylcholine (MPC), 2-((2-(methacryloyloxy)ethyl)dimethylammonio)ethyl methyl phosphate (MMP), and butyl (2-((2-(methacryloyloxy)ethyl)dimethylammonio)ethyl) phosphate (MBP) zwitterions, MPC–PES, MMP–PES and MBP–PES with HSA, FB, and Tr human serum proteins; and (iv) evaluate the effect of different ZW moieties on binding energy and their affinity with human serum proteins. Based on the author’s knowledge, this is the first study to investigate the influence of zwitterion dipole orientation on the interactions of hemodialysis membranes with human serum proteins.

2. Materials and Methods

Molecular Docking Simulation

Molecular docking is a powerful method for predicting protein–ligand interactions between a bimolecular receptor (human serum proteins) and ligand (PES and ZW–PES). Herein, we study the effect of dipole orientation of 2-methacryloyloxyethyl phosphorylcholine (MPC), 2-((2-(methacryloyloxy)ethyl)dimethylammonio)ethyl methyl phosphate (MMP), and butyl (2-((2-(methacryloyloxy)ethyl)dimethylammonio)ethyl) phosphate (MBP) zwitterionic structures, having opposite dipole orientation, on protein–ligand interactions and PES hemocompatibility. The 3D X-ray structures of HSA (PDB code: 1AO6), FB (PDB code: 3GHG), and TRF (PDB code: 1D3K) were downloaded from the RCSB protein data bank (PDB) and used in the docking study. The crystallography ligand, as well as the water molecules and other ions, were removed from the protein chains. The ligand structures were created using ChemDraw software (Version 8.0), and Chem3D Ultra was used for their energy minimization. For energy minimization, the initial ligand geometries were created based on ChemDraw drawings. The ligand structures were then assigned MM2 force field parameters, and the energy was minimized using the optimization algorithm in Chem3D until a convergence criterion was met. The optimized molecular structures (mol format) were converted to PDBQT formats using the AutoDock tools 4.2.6. Molecular docking between human serum proteins and the ligands was performed using AutoDockVina software version 4.0 (Developed by the Scripps Research Institute, La Jolla, CA, USA) to evaluate the optimal structural properties of inherent protein–ligand interactions through molecular prediction [38]. Figure 1 represents the dipole array along the zwitterion structures, which can either be directed toward the backbone of the ZW chain (as in MMP and MBP) or away from the backbone (as in MPC). In addition, the optimized and energy-minimized structures of these ligands and PES are presented in Figure 1. According to the recommended procedure for molecular docking [39], the steps listed below were performed [40]:
(i)
Removing water molecules, ligands, ions, and metal atoms from human serum proteins, downloaded from PDB;
(ii)
Adding Kollman charges;
(iii)
Merging nonpolar hydrogens;
(iv)
Using AutoDock 4 to convert to PDBQT format.
In our molecular docking simulations, we made specific assumptions to ensure the accuracy of our findings. A docking box of size (40 × 40 × 40) Å (illustrating active sites) [35,41,42] was placed around the crystallographic ligand. In order to optimize efficiency, protein residues with atom sizes larger than 7.0 Å were eliminated from the docking box. Utilizing the Lamarckian Genetic Search Algorithm (LGA) [43], 15 computational runs were conducted to ensure the accuracy of the data. The forms of interactions between docked proteins and zwitterionic ligands were determined by measuring the intermolecular energy. To convert mol to PDB format, the PyMOL 2.5.5 (Designed by Schrödinger, LLC, New York, NY, USA) molecular graphics system was used as a potent molecular viewer with remarkable 3D capabilities. Additionally, all the minimized energy conformers were acquired from ChemDraw and presented with ChemDraw, PyMOL, and Discovery Studio Visualizer 21.1.0.20298. By measuring the intermolecular energy of the ligand–protein complex, types of interactions between the docked protein and the ligand were studied through 2D interaction diagrams and ball–stick figure interactions drawn using PyMOL.

3. Results and Discussion

3.1. PES Interactions with Human Serum Proteins

When blood encounters foreign materials, particularly those lacking hemocompatible top layers, it triggers a cascade of interconnected reactions. These include protein adsorption, blood protein activation, platelet adhesion, complement activation, and the onset of blood clots and thrombus formation, culminating in the development of a fibrin matrix [44]. The subsequent accumulation of a protein cake layer on the dialyzer membrane surface can hinder the device’s functionality, potentially leading to various adverse effects and reducing the device’s lifespan. Given these implications, a thorough examination of protein interactions and adsorption on membrane surfaces becomes imperative to enhance membrane hemocompatibility. To further elucidate the underlying mechanisms and interactions that contribute to these phenomena, our study has looked into the interactions between the PES membrane and protein chains, which are pivotal in understanding fouling. The fouling on the PES membrane is primarily attributed to two major interactions: Hydrophilic interactions between certain amino acid residues and the PES membrane. Hydrophobic interactions are caused by protein chains with the PES membrane.
Furthermore, the aqueous environment of the bloodstream, with its varying composition, can influence the behavior of amino acids. This variation can lead to differential binding affinities of proteins to the membrane, resulting in competitive binding scenarios. In our research, we have delved into these competitive binding dynamics, providing insights into how different proteins might compete for binding sites on the membrane, influenced by the specific amino acid residues and their interactions. Molecular modeling has become a valuable and essential tool to medicinal chemists and biomaterial advances as it could effectively estimate the binding sites and binding energy of the protein–ligand complexes [45,46]. In this research, we utilized molecular docking to investigate both pristine and zwitterion-grafted PES membranes in interaction with three critical human serum proteins: HSA, FB, and Tr. We aimed to assess the impact of zwitterion grafting (as depicted in Figure 1) on PES hemocompatibility and to further analyze how dipole orientation influences affinity energy and the dynamics of membrane–protein interactions.
The molecular docking results of the PES membrane model with the active sites of different human serum proteins, including HSA, FB, and Tr, revealed two significant interactions: (1) polar interaction between the etheric and SO2 groups of PES and the hydrophilic parts of proteins; and (2) apolar or hydrophobic interactions between protein constituents and phenyl groups in the PES structure. As shown in Figure 2, according to docking of the PES structure and the HSA, FB, and Tractive sites, the SO2 groups interact with the hydrophilic pockets of proteins as a hydrophilic contact with Arg209, Trp33, Ser189, and Gly190 amino acids. The residues Asp61, Cyc28, Ser31, Ser47, and Arg50 are responsible for other hydrogen bonds. The Phe228, Ala213, Leu327, Leu347, Leu481, Gly328, Leu331, Ala210, Val216, Ala350, Val482, Val215, Leu481, Val74, Ala27, Gly28, Trp33, Ala59, Leu72, Pro70, Leu66, Leu293, Leu294, Gly190, Ala191, Phe186, Tyr188, and Thr181 pockets that surround the phenyl groups in the PES model are also considered hydrophobic interactions of this molecule. Therefore, PES has more hydrophobic interactions than hydrophilic ones and fits better in the hydrophobic moiety. Docking analysis showed that PES ligand interactions with albumin protein had maximum binding energies of −10.3 kcal/mol, while interactions with FB and Tr proteins had binding energies of −8.5 kcal/mol and −9.2 kcal/mol, respectively.
It should be noted that in the docking of PES with HSA, FB, and Tr, the phenyl ring of the middle site interacts with the Thr181, Ala213, Ala 350, Leu347, Val74, Cys28, Asp30, Asp 61, and Phe186, which, in turn, are responsible for Pi-Sigma, Pi-Alkyl, Pi-Pi, and Pi-Sulfur noncovalent interactions. Several other amino acids, including Ala59, Ala210, Val482, Lys212, Lys193, Gln184, Leu293, Lys351, and Lys 296, could interact hydrophobically with the other phenyl groups. Table 1 summarizes the results of the interactions between the PES membrane model and HSA, FB, and Tr.

3.2. Influence of Dipole Orientation of ZW on the Interactions with Human Serum Proteins

Molecular docking was performed first on the proposed ZWs before the zwitterionization of the PES membrane model to examine the impact of dipole orientation on ZW interactions, followed by the evaluating of ZW–PES interactions. MPC is a bio-inspired zwitterionic structure with extensive hydrophilicity, hemocompatibility, and antifouling qualities, which has strong potential applicability for drug delivery systems and biomedical devices [47,48,49].
The choline phosphates (like MBP and MMP) that result from reversing this zwitterionic structure (MPC) have a wide range of structural diversity and interactions [50]. Figure 3 represents the energy-minimized conformation of MMP and MPC.
Docking results of the MMP and MPC with HSA, FB, and Tr were presented in Figure 4 and Figure 5. PyMOL and Discovery Studio Visualizer illustrations showed significant differences between optimized structures with minimized energies for MMP and MPC (Figure 3). While MPC displayed a linear conformation at the lowest energy level, MMP presented a shrinkage conformation. This indicates that MMP chains have stronger electrostatic dipole–dipole interactions, which can lead to more self-assembly in this ZW chain. Furthermore, it leads to the formation of a stronger hydration shell with H2O molecules, which improves antifouling and hemocompatibility properties. Docking studies showed that MPC had higher affinity energies for all the ligand–protein interactions compared to MMP. As presented in Table 2, MPC binds to the active sites of HSA, FB, and Tr, with affinities of −6, −5.9, and −5.7 kcal/mol, respectively, whereas MMP binds with lower affinities of −5.5, −4.9, −4.6 kcal/mol. As a purely helical protein, with 67% helices in its secondary structure and 585 amino acids in its primary sequence, the ZW ligands (MMP and MPC) bind to the polar sites of HSA with a higher affinity binding interaction than FB and Tr. The amino acids Leu347, Gly328, Ala350, Leu327, Gly354, Leu331, Ala210, and Ala213 were engaged in hydrophobic interaction between MMP and HSA, as presented in Figure 5. Furthermore, the Leu481, Val482, Ser480, Asp324, Arg209, and Lys35 interacted in a hydrophilic manner with MMP. On the other hand, MPC had polar interactions with HAS via Glu153, Glu292, Lys199, Arg222, Arg257, His 242, Ser192, and Lys195, which occured from different polar positions. Thr181, Phe192, Ser189, Asn213, Gln184, Gly290, and Leu293 are further examples of MPC–HSA hydrophobic interactions. According to the 2D interactions figures, in the MMP model, the hydrogen bonds formed between the oxygen atom of the phosphate group and Leu481 and Val482, while in the MPC model, hydrogen bonds formed between the O atoms of the phosphate and also the acrylate part (owing to its linear conformation and the availability of O atoms in both sites) and Arg222, Lys 195, and Lys 199. Even though MPC seems to have more and also stronger hydrogen bonds than MMP, which typically leads to a stronger hydrophilicity shell and lower fouling property, it demonstrated higher affinity energy for binding to HSA. This phenomenon can be attributed to additional interactions between MPC and HSA, notably the salt bridge. This interaction is the strongest noncovalent molecular contact between oppositely charged residues that keep the ligand–protein in the closed conformation. In the MPC model, salt bridge interactions arise between the oxygen atom of the phosphate and the positively charged nitrogen of the ammonium group, specifically engaging with the Arg222, Lys195, Lys199, Glu153, and Glu292 amino acids of HSA. It is noteworthy that molecular docking revealed no salt bridge interaction between MMP and HSA.
This underscores that variations in ligand conformation, driven by dipole orientation, play a pivotal role in determining the interactions between proteins and ligands. Consequently, the MPC model ligand exhibits a greater number of both hydrophobic and hydrophilic interactions when binding to HSA, accounting for its elevated affinity binding energy compared to MMP. These observations align with experimental findings documented in the literature [51]. Table 2 provides a comprehensive overview of the docking results and interactions between HSA, FB, and Tr with both MMP and MPC. It should be mentioned that various optimized conformations of MMP and the MPC have also resulted in different interactions with other proteins (FB and TR), resulting in different hydrophobic and hydrophilic interactions and varying affinity energies, as presented in Table 2.
Furthermore, we have performed molecular docking on n-butyl-substituted choline phosphate monomer (MBP), reported by Morozova et al. [50,51] as a feasible candidate for experimental studies. MBP represents a different dipole orientation compared to MPC, as presented in Figure 6. Additionally, MBP has a n-butyl group rather than the methyl group present in MMP, which can be used to compare the effect of dipole orientation versus hydrophilic group on hemocompatibility. Because of the increased hydrophobicity caused by the n-butyl groups, it is anticipated that MBP would differ from its counterparts in terms of dielectric constant, hydrophilicity/hydrophobicity imbalance, and other properties. However, MBP showed a shrinkage structure at minimized energy, similar to MMP (Figure 6). The docking results showed that the affinity energies of MBP binding to HSA, FB, and Tr were −5.6, −4.9, and −4.7, respectively, which are very similar to those of MMP (Figure 7 and Table 2). Comparing MBP and MPC revealed that MPC had higher binding affinity energy to human serum proteins, indicating that MPC is less hemocompatible. Since MBP contains an n-Bu group, its lower affinity energy indicates that the dipole orientation contributes more to fouling resistance and hemocompatibility than the existing hydrophobic groups. Table 2 summarizes the molecular docking computation results, including the affinity energy and different interactions between MBP and human serum proteins.
Despite the fact that MPC has been used in a variety of bio-related materials, choline phosphates (such as MBP) with reverse structures possess greater variability and more tunable properties than MPC. They are well-known hydrophilic molecules that have been used for antibiofouling applications across a wide range of industries [52,53,54].

3.3. ZW–PES Membrane Models Interactions with Human Serum Proteins

This computational study has been extended to examine the interactions between MBP–PES, MMP–PES, and MPC–PES membrane models (Figure 8) with HSA, FB, and Tr to evaluate the impact of these ZWs with the opposite dipole orientation on the membrane hemocompatibility. Data from docking studies showed that the MPC–PES model had a higher binding affinity than the MBP–PES and the MMP–PES models, as well as different interaction patterns for each of the proteins (Figure 9, Figure 10 and Figure 11 and Table 3). When ZW–PES membrane models docked into the protein active sites, two significant interactions were observed: (1) polar interactions induced by ZW and SO2 groups and (2) hydrophobic interactions caused by protein chains with the PES membrane.
According to the docking result of the MMP–PES model with HSA protein (Figure 9), Leu115, His145, Ser193, Asp108, Pro110, Ile523, and Arg145 are amino acids involved in hydrophilic interactions. While, in hydrophobic interactions, Tyr138, Ile142, Ala194, Pro147, Leu463, Gln459, Asn109, Pro110, Ile 523, and Val424 were responsible residues. MMP showed a potentially positive effect on the antifouling property of PES by reducing the interaction affinity energy to −8.6 kcal/mol with HSA protein (Table 3, entry 1), compared to the interaction affinity energy of −10.3 kcal/mol between PES ligand and HSA protein (Table 1, entry 1).
On the other hand, MPC–PES docking into the HSA active site also revealed hydrophobic and hydrophilic interactions as the main interactions between protein and ligand. The Lys137, Leu115, Ile142, Tyr138, Met123, Clu141, Lys137, Tyr161, Leu182, Asn109, Leu463, Val462, Pro147, Gln459, Ala194, and Pro110 amino acids were expected to have hydrophobic contact with MPC–PES, while Arg186, Arg114, Lys137, Ser193, Arg117, Arg197, and Arg145 were responsible for the formation of hydrogen bonds, and Asp108, His146, and Lys190 were involved in attractive charge interactions as polar contacts (Figure 10). The binding energy values of MPC–PES with all the examined proteins were in the range between the binding energy values of interaction between PES and MPC alone, indicating that even though MPC structure had a significant effect on PES hemocompatibility improvement, it was not as much as MPC alone because of PES hydrophobic interactions.
As shown in Figure 11a–c images, docking studies were also performed on MBP–PES with HSA to explore the potential impact of the n-Bu group and the impact of dipole orientation as a key feature of ZW chains on PES hemocompatibility. Docking simulation with the HSA protein and MBP–PES chain showed the residues responsible for hydrophobic pocket, concluding MBP–PES model ligands are Tyr452, Val455, Ala191, Cys448, Trp214, Val293, Glu292, Pro447, His288, Asp451, Phe157, Leu198, Pro339, and Ser 192. According to the results shown in Figure 11a–c images, the zwitterion was bound to HSA via hydrogen bonding by interacting with Asn295, Arg218, Lys436, Glu292, Lys195, and Arg222. Nonspecific interactions like hydrophobic contacts and other electrostatic attractions could be distinguished between ligand and HSA protein. The binding energy of the PES model interaction with HSA was found to be −10.3 kcal/mol, and it was found to be −5.7 kcal/mol for the interaction between MBP and HSA. The binding energy of ZW-modified PES (MBP–PES) was found to be −8.5 kcal/mol, demonstrating the impact of ZW on the improvement of PES hemocompatibility (Table 3, entry 3). The interaction affinity energy of MBP–PES with FB and Tr was close to the MMP–PES ligand, which demonstrated that the n-Bu group has no significant influence in this study. In comparison, MBP–PES exhibited four hydrogen bonds with the active sites of HSA, while MPC–PES only showed two, which plays an important role in hemocompatibility. The stronger hydrogen shell of MBP–PES was, therefore, anticipated to make it a more compatible ligand. When MPC–PES was docked with HSA, it was found that this ligand had higher affinity energy (−9.2 kcal/mol) compared to MBP–PES as well as different protein–ligand interactions, which indicates that it is more likely to have fewer antifouling and hemocompatibility properties in experimental situations. This trend represents evidence when ligands were docked with FB and Tr; in both cases, MPC–PES showed an approximately 1 kcal/mol higher affinity energy than MBP–PES.
Typically, zwitterionic materials display distinctive behaviors as a result of their dipole moments. As dipole–dipole interactions are electrostatic bindings, many parameters, such as ZW conformations, optimal structures, or experimental circumstances that alter electrostatics, can affect the assembly processes using zwitterionic compounds [51,55]. There is no question that almost all proteins (including HSA, FB, and Tr) possess charged amino acids that subsequently influence electrostatic protein–ligand interactions and bind to individual charges in the active sites of the ligand in different manners [56]. So, energy affinity differences between zwitterions with similar structures but different dipole orientations can be explained by a combination of electrostatic interactions, such as charge–charge, charge–dipole, and dipole–dipole interactions of the ligand and the impact of protein charge ladders, which, in turn, has a significant effect on the compatibility and fouling properties. It is worth noting that the opposite dipole orientations of the studied zwitterions have shown different accessibility of charged sites. This can be attributed to the different optimized conformations (Figure 8), which resulted in various electrostatic interactions with human proteins, even overriding some structural differences like the n-butyl group and its effect on the hydrophilicity/hydrophobicity balance. In general, the performance of the zwitterions is influenced by the dipole density, dipole orientation and length, pendant group identity, conformation, and local dielectric characteristics, which serves as evidence for the hypothesis of the study [16,17,27,28,51,57,58].
As a result of our findings, all ZW–PES membranes were significantly more hemocompatible than pristine PES, demonstrating the influence of ZW chains regardless of their dipole moment (Table 3). It should be emphasized that even though adding neutral zwitterionic materials to the PES membrane enhanced biocompatibility, the etheric and sulfone groups of PES also significantly influenced protein–ligand interactions (Figure 9, Figure 10 and Figure 11). In addition, it is noteworthy that the opposite dipole orientations of the MBP and MPC showed different accessibility of charged sites, possibly as a result of different optimized conformations, which leads to different electrostatic interactions with proteins and different compatibilities of PES, as indicated by affinity energy results.

4. Conclusions

Zwitterions, characterized by their pronounced dipole moments, play a pivotal role in molecular interactions. Their inherent ability to form diverse dipole–dipole connections translates into unique hemocompatibility properties, which are of paramount importance in biomedical applications. Given the inherent challenges associated with traditional medical experimentation—both in terms of cost and time—computational simulations emerge as an invaluable tool. These simulations not only offer predictive insights but also present a strategic pathway for optimizing research resources. By harnessing the power of computational simulations, researchers can delve deeper into the molecular dynamics of zwitterions, understanding their behavior in various environments. This, in turn, paves the way for the development of more efficient and targeted biomedical materials, ensuring safer and more effective outcomes for patients.
In this research, we conducted a comprehensive computational analysis focused on the PES membrane, a prevalent hemodialysis membrane extensively utilized across Canadian healthcare institutions. Our primary objective was to delve into the nuanced effects of segmental dipolar orientations within zwitterion chains on the PES membrane’s hemocompatibility and antifouling attributes. This investigative approach is pioneering, marking the first endeavor to understand these effects in this context. To elucidate the influence of dipole orientation on the hemocompatibility of PES, we strategically selected zwitterionic structures that exhibited contrasting dipole moments (Figure 12). These structures were meticulously examined both in their isolated states and in combination with PES to provide a holistic understanding of their interactions. Our findings were revealing: structures such as MMP and MBP, which share a common dipole orientation, consistently demonstrated reduced affinity energies for all proteins under scrutiny when compared to MPC, which possesses an opposing dipole orientation.
The result showed that the MBP–PES structure was by far the best candidate, showing fewer interactions with serum proteins of HSA, FB, and Tr when compared with others. The affinity bindings demonstrated that these differences were shown more strongly for FB and TR but not for HSA (Figure 13).
Three reasons make MBP and MPC excellent candidates for further experimental research, including (1) their synthetic procedure and chemical, (2) the presence of an aliphatic group (n-butyl), which allows us to compare the effects of dipole orientation versus hydrophobic substitution; moreover, (3) MBP and MPC have been previously reported, allowing us to compare our computational results with the experimental findings [50,51]. It should be emphasized that all of the MMP–PES results were displayed in Table 3, demonstrating how closely the docking results and affinity energies for the two mentioned ligands (MMP–PES and MBP–PES). Given the foregoing logic, it is reasonable to evaluate MBP–PES rather than MMP–PES.
In our study, the affinity energy derived from computational docking has emerged as a powerful metric, offering profound insight into membrane hemocompatibility and fouling resistance. This approach not only presents a cost-effective alternative to traditional, resource-intensive experimental methods but also holds significant promise for guiding future experimental endeavors. The data from our computational models are invaluable for several reasons. Firstly, it provides predictive insights into the intricate behavior of zwitterions and their interactions with the PES membrane, empowering experimentalists with the knowledge to design superior membranes and understand protein interactions more deeply. Secondly, in the often resource-intensive realm of medical research, our computational approach offers a pathway to greater efficiency, potentially reducing the time and financial burdens associated with experimental trials. Lastly, our findings serve as a roadmap, pinpointing areas ripe for further exploration and, thereby, aiding experimentalists in focusing their efforts more effectively. In essence, our computational methods not only streamline the research process but also pave the way for groundbreaking advancements in the field. The resulting affinity energy via computational docking could provide valuable information regarding the membrane hemocompatibility and fouling resistance in a cost-effective manner rather than time- and energy-consuming trial-and-error experiments.
Based on the obtained results, our future scope entails a focused effort on experimental work to synthesize the most promising membrane materials derived from these findings. We will then proceed to conduct comprehensive hemocompatibility testing to ensure that these materials meet the highest standards of safety and performance, contributing to the advancement of membrane separation technologies.

Author Contributions

Conceptualization and methodology, A.A.; Computation and formal analysis, S.N. under supervision of A.A.; writing—original draft preparation, S.N.; writing—review and editing, A.A. All authors have read and agreed to the published version of the manuscript.

Funding

Natural Sciences and Engineering Research Council (NSERC).

Institutional Review Board Statement

Not Applicable.

Informed Consent Statement

Not Applicable.

Data Availability Statement

The raw/processed data required to reproduce these findings cannot be shared at this time, as the data is critical to the ongoing research.

Conflicts of Interest

The authors declare no conflict of interest.

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Figure 1. Structures, stick view (with energy minimization), and dipole orientation of polyethersulfone (PES) and zwitterion chains (MMP and MPC).
Figure 1. Structures, stick view (with energy minimization), and dipole orientation of polyethersulfone (PES) and zwitterion chains (MMP and MPC).
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Figure 2. (a) 2D interaction diagrams, (b) 3D images, and (c) electrostatic maps of interactions of docking PES with HSA, FB, and Tr.
Figure 2. (a) 2D interaction diagrams, (b) 3D images, and (c) electrostatic maps of interactions of docking PES with HSA, FB, and Tr.
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Figure 3. Minimized-energy structure of MMP and MPC zwitterions with (a) PyMOL and (b) Discovery Studio Visualizer.
Figure 3. Minimized-energy structure of MMP and MPC zwitterions with (a) PyMOL and (b) Discovery Studio Visualizer.
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Figure 4. (a) 2D interaction diagrams, (b) 3D images of docking MMP ligand–proteins interactions, and (c) electrostatic maps of interactions.
Figure 4. (a) 2D interaction diagrams, (b) 3D images of docking MMP ligand–proteins interactions, and (c) electrostatic maps of interactions.
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Figure 5. (a) 2D interaction diagrams, (b) 3D images of docking MPC ligand–proteins interactions, and (c) electrostatic maps of interactions.
Figure 5. (a) 2D interaction diagrams, (b) 3D images of docking MPC ligand–proteins interactions, and (c) electrostatic maps of interactions.
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Figure 6. Dipole orientation (a) and minimized energy structure of MBP zwitterion by (b) PyMOL and (c) Discovery Studio Visualizer.
Figure 6. Dipole orientation (a) and minimized energy structure of MBP zwitterion by (b) PyMOL and (c) Discovery Studio Visualizer.
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Figure 7. (a) 2D interaction diagrams, (b) 3D images of docking MBP ligand–protein interactions, and (c) electrostatic maps of interactions.
Figure 7. (a) 2D interaction diagrams, (b) 3D images of docking MBP ligand–protein interactions, and (c) electrostatic maps of interactions.
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Figure 8. Optimized conformations of (a) MMP–PES, (b) MPC–PES, and (c) MBP–PES.
Figure 8. Optimized conformations of (a) MMP–PES, (b) MPC–PES, and (c) MBP–PES.
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Figure 9. Molecular docking of the interaction between the HSA, FB, and TR proteins and the MMP–PES ligand; (a) 3D images, (b) 2D interaction diagrams, and (c) 3D docking poses with ball–stick figures indicating polar interactions with important contributing amino acids (Draw by Discovery Studio Visualizer).
Figure 9. Molecular docking of the interaction between the HSA, FB, and TR proteins and the MMP–PES ligand; (a) 3D images, (b) 2D interaction diagrams, and (c) 3D docking poses with ball–stick figures indicating polar interactions with important contributing amino acids (Draw by Discovery Studio Visualizer).
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Figure 10. Molecular docking of the interaction between the HSA, FB, and TR proteins and the MPC–PES ligand; (a) 3D images, (b) 2D interaction diagrams, and (c) 3D docking poses with ball–stick figures indicating polar interactions with important contributing amino acids (Draw by Discovery Studio Visualizer).
Figure 10. Molecular docking of the interaction between the HSA, FB, and TR proteins and the MPC–PES ligand; (a) 3D images, (b) 2D interaction diagrams, and (c) 3D docking poses with ball–stick figures indicating polar interactions with important contributing amino acids (Draw by Discovery Studio Visualizer).
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Figure 11. Molecular docking of the interaction between the HSA, FB, and TR proteins and the MBP–PES ligand; (a) 3D images, (b) 2D interaction diagrams, and (c) 3D docking poses with ball–stick figures indicating polar interactions with important contributing amino acids (Draw by Discovery Studio Visualizer).
Figure 11. Molecular docking of the interaction between the HSA, FB, and TR proteins and the MBP–PES ligand; (a) 3D images, (b) 2D interaction diagrams, and (c) 3D docking poses with ball–stick figures indicating polar interactions with important contributing amino acids (Draw by Discovery Studio Visualizer).
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Figure 12. All the utilized zwitterions.
Figure 12. All the utilized zwitterions.
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Figure 13. Affinity energy ranked results of docking PES. MBP, MPC, MBP–PES, and MPC–PES with HSA, FB, and TR proteins.
Figure 13. Affinity energy ranked results of docking PES. MBP, MPC, MBP–PES, and MPC–PES with HSA, FB, and TR proteins.
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Table 1. Binding energy and receptor contacts of HSA, FB, and Tr interactions with PES.
Table 1. Binding energy and receptor contacts of HSA, FB, and Tr interactions with PES.
LigandProteinBinding Energy (kcal/mol)Receptor Contacts
HydrophilicHydrophobic
PESHSA−10.3Arg209, Glu354 *, Lys351 *, Ser480 *, Lys212 *, Asp324 *.Leu347, Ala350, Val 482, Ala213, Leu327, Val216, Phe228, Gly328, Leu 331, Ala210, Val215, Leu481
PESFB−8.5Asp61, Trp33, Cys28, Ser31, Ser47, Arg50, Lys29 *, Cys49 *, Cys76 *, Lys58 *, Asp30 *.Ala59, Ala27, Val74, Gly28, Trp33, Leu72, Pro70, Leu66
PESTr−9.2Ser189, Gly190, Glu15 *, Arg124 *, Lys296 *, His249 *, Asp292 *, Lys193 *, Glu83 *, Lys291 *.Phe186, Leu293, Leu294, Thr61, Phe295, Tyr188, Gly187, Thr181, Gln184, Gly190, Ala191
*: Weak Van der Waals interactions.
Table 2. Binding energy results and receptor contacts of HSA, FB, and Tr interactions with MMP, MPC, and MBP zwitterions.
Table 2. Binding energy results and receptor contacts of HSA, FB, and Tr interactions with MMP, MPC, and MBP zwitterions.
LigandProteinBinding Energy (kcal/mol)Receptor Contacts
HydrophilicHydrophobic
MMPHSA−5.5Leu481, Val482, Ser480, Asp324 a, Arg209 a, Lys35 a.Leu347, Gly328, Ala350, Leu327, Gly354, Leu331, Ala210, Ala213
MMPFB−4.9Arg50, Ser47, Asp61, Ala27 a.Val74, Cys49 b, Cys28 b, Cys76 b, Ala59 b,Lys29 b
MMPTr−4.6Lys291, Lys196, Leu293 a, His289 a, His 14 a, Ser189 a.Thr181 b, Phe192 b, Ser189 b, Asn213 b, Gln184 b, Gly290 b, Leu293 b
MPCHSA−6Glu153, Glu292, Lys199, Lys195, Arg222, Arg257 a, His242 a, Trp214 a, Ser192 a.Ala291, Phe223, Ile264, Leu234, Leu260 b, Leu219 b, Leu238 b, Ile290 b, Trp214, Gln196 a
MPCFB−5.9Asp61, Arg50, Val74, Cyc49 a, Cys28 a, Ser47 a.Gly73, Trp33
MPCTr−5.7Glu15, Arg124, Tyr188, Ser189, His249, Lys296 a, Gly190 a, Gly187 a, Val11 a, Leu62 a, Tyr45 a, Leu66 a, Asp63 a, Lys296 a.Thr61, Thr181, Phe186, Asp292
MBPHSA−5.6Glu354, Arg209, Lys351, Asp324 a, Leu327 a, Ala350 a, Leu347 a, Ser480 a, Val482 a, Ala210 a, Leu331 a, Gly328 a, Ala213 a.Val216, Lys212, Leu481, Phe206.
MBPFB−4.9Asp61, Arg50, Ser47, Ala27 a, Cyc49 a,
Asp30 a, Trp33 a, Cys49 a, Cys76 a, Ser47 a, Cys28 a.		Val74, Cys28 b.
MBPTr−4.7Tyr238, Lys276, His300, Ser208 a, Ser298 a, Glu212 a, Ser286 a, Lys291 a, Asp297 a, Tyr85 a, Asp236 a.Gly86, Phe285, Phe211 b
a: Weak Van der Waals, b: Alkyl interactions.
Table 3. Binding energy results and receptor contacts of HSA, FB, and Tr interactions with MMP–PES, MPC–PES, and MBP–PES models.
Table 3. Binding energy results and receptor contacts of HSA, FB, and Tr interactions with MMP–PES, MPC–PES, and MBP–PES models.
LigandProteinBinding Energy (kcal/mol)Receptor Contacts
HydrophilicHydrophobic
MMP–PES HSA−8.6Leu115, His145, Ser193, Asp108 a, Arg145 a, Lys190, Glu141 a, Arg186 a, Arg428 a, Glu425 b, Arg145 b.Tyr138, Ile142, Ala194, Pro147, Leu463, Gln459, Asn109, Pro110, Ile523, Val424
MMP–PES FB−6.6Ser47, Arg 50 a, Asp61 a, Lys58 a, Lys29 a, Asp61 b, Arg50 b.Cys28, Trp33, Cys49, Cys76, Val74, Ala59, Pro70, Leu66, Ala68, Leu 72, Cys28, Gly 73
MMP–PES TR−6.2Ser286, Lys276, Asp236 a, Arg220 a, Lys291 a, Tyr238, Glu212 b, Asp297 b.Phe211, His300, Phe285, Gln283, Gly86, His207, His208
MPC–PES HSA−9.2Arg186, Arg114, Arg117 a, Lys137 a, Arg145 a, Arg197 a, Ser193 a,
Asp108 b, His146 b, Lys190 b.		Leu115, Ile142, Tyr138, Met123, Clu141, Lys137, Tyr161, Leu182, Asn109, Leu463, Val462, Pro147, Gln459, Ala194, Pro110
MPC–PES FB−7.3Ala27, Ser47, Val74, Lys58 a, Lys29 a, Asp69 a, His67 a.Ala59, Leu72, Ala68, His67, Leu66, Val74, Ala59, Trp33, Cys49, Pro70
MPC–PES TR−7.2His207, Tyr238, Lys291, Lys276, Gln92, Glu212 a, Asp236 a,Asp297 a, Asp90 b, Lys239 b.Phe211, Gly86, Ser286, Ser287, Ser87, Tyr96, Ser208, His300, Ser298,
MBP–PES HSA−8.5Asn295, Arg218, Lys436, Arg222, Lys444 a, Glu292 a, Lys195 a.Tyr452, Phe157, Cys448, Trp214 c, Val293, Pro447, His288, Asp451 c, Leu198, Pro339, Ala191, Val455, Ser 192
MBP–PES FB−6.3Ser31, Asp61 a, Lys29 a, Arg50 a, Asp61 b, Arg50 b, Ser47Ala59, Pro70, Pro60, Trp33, Met51, Cys28, Cys49, Val74, Leu66, Gly73.
MBP–PES TR−6.2His300, Gln92, Tyr238, Glu212 a, Lys276 a, Lys219 a, Asp90 b, His207 b, Lys239 b.Phe285, Ser208, Tyr90, Tyr85, Tyr96, Gly86, Asp297 c, Ser87, Phe211 c.
a: Weak Van der Waals, b: Attractive Charge, c: Pi–Pi Interactions.
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Nazari, S.; Abdelrasoul, A. Influence of Dipole Orientation of Zwitterionic Materials on Hemodialysis Membrane Interactions with Human Serum Proteins. Appl. Sci. 2023, 13, 12777. https://doi.org/10.3390/app132312777

AMA Style

Nazari S, Abdelrasoul A. Influence of Dipole Orientation of Zwitterionic Materials on Hemodialysis Membrane Interactions with Human Serum Proteins. Applied Sciences. 2023; 13(23):12777. https://doi.org/10.3390/app132312777

Chicago/Turabian Style

Nazari, Simin, and Amira Abdelrasoul. 2023. "Influence of Dipole Orientation of Zwitterionic Materials on Hemodialysis Membrane Interactions with Human Serum Proteins" Applied Sciences 13, no. 23: 12777. https://doi.org/10.3390/app132312777

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