Molecular Structure and Simulation in Biological System

A special issue of Biophysica (ISSN 2673-4125).

Deadline for manuscript submissions: closed (16 March 2023) | Viewed by 15884

Special Issue Editor

Special Issue Information

Dear Colleagues,

Structural information at the atomic scale of macromolecules allows a precise understanding of the mechanisms underlying different types of biological system, including intermolecular interactions, intracellular interactions, and so on.

Knowledge of this information, as well as techniques capable of computationally simulating the movement of these macromolecules in their biological system, helps us to rationalize the mechanisms and understand how biological systems work.

This Special Issue welcomes papers using 3D molecular structure and/or virtual modeling techniques in computational biology, alone or in combination with in vitro or in vivo strategies. The aim of these techniques may be the prevention, discovery, characterization or therapy of diseases, including cancers, genetic diseases, or those related to viral or bacterial infections. We also welcome papers addressing 3D screening strategies, the design of new drugs and therapies and any original articles or comprehensive reviews related to molecular structure and simulation in biological system.

Dr. Paulino Gómez-Puertas
Guest Editor

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Keywords

  • macromolecular structure
  • computational biology
  • drug design
  • molecular dynamics
  • virtual modeling

Published Papers (10 papers)

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Research

9 pages, 2411 KiB  
Article
The Dynamic Behavior of a Single Semiflexible Ring Chain in a Linear Polymer Matrix
by Xiaolin Zhou and Yifan Qin
Biophysica 2023, 3(3), 476-484; https://doi.org/10.3390/biophysica3030031 - 26 Jul 2023
Viewed by 705
Abstract
We studied the dynamic behavior of a single semiflexible ring in linear chain matrix based on a coarse-grained model using the molecular dynamics simulation approach. We found that that ring chains’ hollow centers are frequently filled with linear chains. However, as the rigidity [...] Read more.
We studied the dynamic behavior of a single semiflexible ring in linear chain matrix based on a coarse-grained model using the molecular dynamics simulation approach. We found that that ring chains’ hollow centers are frequently filled with linear chains. However, as the rigidity of the linear chains increases, the linear chains arranged parallel to each other and the ring chain are temporary caged. As a result, the swing movement in the normal direction of the ring is significantly limited, and the relaxation time in the normal direction increases significantly. Our findings can help to understand the physical mechanism of the movement of the ring chain in ring–linear polymer blends at the microscopic level. Full article
(This article belongs to the Special Issue Molecular Structure and Simulation in Biological System)
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21 pages, 4004 KiB  
Article
Screening for Bioactive Metabolites in Leaves, Branches, and Roots of Mansoa hirsuta: Phytochemical, Toxicological and Antioxidant Aspects
by Patrícia e Silva Alves, Gagan Preet, Maria Oliveira, Leandro Dias, Giovanna Silva, Maria Luísa Nascimento, Antonielly Reis, João Marcelo Sousa, Joaquim Júnior, Nerilson Marques Lima, Teresinha Andrade and Chistiane Feitosa
Biophysica 2023, 3(3), 425-445; https://doi.org/10.3390/biophysica3030028 - 28 Jun 2023
Cited by 1 | Viewed by 1349
Abstract
In this study, secondary metabolites, toxicology and antioxidant properties of chloroform fractions from leaves (FCFMh), branches (FCGMh), and roots (FCRMh) of Mansoa hirsuta were investigated. The phytochemical screening detected flavonoids, especially chalcones. Through Liquid chromatography with mass spectrometry—LC–MS analysis, the flavonoids (isoorientin-2″-O [...] Read more.
In this study, secondary metabolites, toxicology and antioxidant properties of chloroform fractions from leaves (FCFMh), branches (FCGMh), and roots (FCRMh) of Mansoa hirsuta were investigated. The phytochemical screening detected flavonoids, especially chalcones. Through Liquid chromatography with mass spectrometry—LC–MS analysis, the flavonoids (isoorientin-2″-O-arabinoside), triterpenes (oleanolic acid and ursolic acid) and ceramide (phytosphingosine) were identified. From the Artemia salina assay, the fraction FCGMh was the most toxic (LC50 = 64.21 µg·mL−1), followed by FCRMh (LC50 = 87.61 µg·mL−1) and FCFMh (LC50 = 421.9 µg·mL−1). Concerning the cytotoxic potential, the root fraction (IC50 16.48 μg mL−1) displayed the highest cytotoxicity against the breast cancer cell line (4T1), followed by leaves (IC50 33.13 μg mL−1) and branches (IC50 of 47.13 μg mL−1). In conclusion, all the fractions of M. hirsuta showed cytotoxicity at the highest concentrations; however, remarkable biological properties were found for the root fractions. Computational analysis was performed using a molecular docking and pharmacophore approach to understand the antioxidant activity of its major metabolites. Full article
(This article belongs to the Special Issue Molecular Structure and Simulation in Biological System)
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24 pages, 4160 KiB  
Article
A Two-Species Finite Volume Scalar Model for Modeling the Diffusion of Poly(lactic-co-glycolic acid) into a Coronary Arterial Wall from a Single Half-Embedded Drug Eluting Stent Strut
by Rodward L. Hewlin, Jr., Maegan Edwards and John P. Kizito
Biophysica 2023, 3(2), 385-408; https://doi.org/10.3390/biophysica3020026 - 15 Jun 2023
Viewed by 1251
Abstract
This paper outlines the methodology and results for a two-species finite volume scalar computational drug transport model developed for simulating the mass transport of Poly(lactic-co-glycolic acid (PLGA)) from a half-embedded single strut implanted in a coronary arterial vessel wall. The mathematical drug transport [...] Read more.
This paper outlines the methodology and results for a two-species finite volume scalar computational drug transport model developed for simulating the mass transport of Poly(lactic-co-glycolic acid (PLGA)) from a half-embedded single strut implanted in a coronary arterial vessel wall. The mathematical drug transport model incorporates the convection-diffusion equation in scalar form (dimensionless) with a two-species (free-drug and bound-drug) mass transport setup, including reversible equilibrium reaction source terms for the free and bound-drug states to account for the pharmaco-kinetic reactions in the arterial wall. The relative reaction rates of the added source terms control the interconversion of the drug between the free and bound-drug states. The model is solved by a 2D finite-volume method for discretizing and solving the free and bound drug transport equations with anisotropic vascular drug diffusivities. This model is an improvement over previously developed models using the finite-difference and finite element method. A dimensionless characteristic scaling pre-analysis was conducted a priori to evaluate the significance of implementing the reaction source terms in the transport equations. This paper reports the findings of an investigation of the interstitial flow profile into the arterial wall and the free and bound drug diffusion profiles with a parametric study of varying the polymer drug concentration (low and high), tortuosity, porosity, and Peclet and DamKöhler numbers over the course of 400 h (16.67 days). The results also reveal how a single species drug delivery model that neglects both a reversible binding reaction source term and the porosity and tortuosity of the arterial wall cannot accurately predict the distribution of both the free and bound drug. Full article
(This article belongs to the Special Issue Molecular Structure and Simulation in Biological System)
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12 pages, 4679 KiB  
Article
Computational Modeling of the Neurofibromin-Stimulated Guanosine Triphosphate Hydrolysis by the KRas Protein
by Igor Polyakov and Alexander Nemukhin
Biophysica 2023, 3(2), 373-384; https://doi.org/10.3390/biophysica3020025 - 31 May 2023
Cited by 2 | Viewed by 1286
Abstract
We report the results of computational studies of the guanosine triphosphate (GTP) hydrolysis in the active site of the KRas-NF1 protein complex, where KRas stands for the K-isoform of the Ras (ras sarcoma) protein and NF1 (neurofbromin-1) is the activating protein. The model [...] Read more.
We report the results of computational studies of the guanosine triphosphate (GTP) hydrolysis in the active site of the KRas-NF1 protein complex, where KRas stands for the K-isoform of the Ras (ras sarcoma) protein and NF1 (neurofbromin-1) is the activating protein. The model system was constructed using coordinates of heavy atoms from the crystal structure PDB ID 6OB2 with the GTP analog GMPPNP. Large-scale classical molecular dynamics (MD) calculations were performed to analyze conformations of the enzyme-substrate complexes. The Gibbs energy profiles for the hydrolysis reaction were computed using MD simulations with quantum mechanics/molecular mechanics (QM/MM) interaction potentials. The density functional theory DFT(ωB97X-D3/6-31G**) approach was applied in QM and the CHARMM36 force field parameters in MM. The most likely scenario of the chemical step of the GTP hydrolysis in KRas-NF1 corresponds to the water-assisted mechanism of the formation of the inorganic phosphate coupled with the dissociation of GTP to GDP. Full article
(This article belongs to the Special Issue Molecular Structure and Simulation in Biological System)
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11 pages, 1861 KiB  
Article
Decomposition of Small Molecules for Fragment-Based Drug Design
by Nikita N. Ivanov, Dmitry A. Shulga and Vladimir A. Palyulin
Biophysica 2023, 3(2), 362-372; https://doi.org/10.3390/biophysica3020024 - 24 May 2023
Viewed by 2331
Abstract
In the drug design process, a frequent task is the decomposition of small molecules into fragments. There exist a number of approaches and methods to break molecules into fragments. However, a method that allows the decomposition of molecules into non-overlapping fragments that is [...] Read more.
In the drug design process, a frequent task is the decomposition of small molecules into fragments. There exist a number of approaches and methods to break molecules into fragments. However, a method that allows the decomposition of molecules into non-overlapping fragments that is meaningful in terms of medicinal chemistry is absent, and in this work, we present a new simple approach for the decomposition of molecules—MedChemFrag. It aims to break drug-like molecules into a set of rings and linkers, which are close to the perception of “fragments” by medicinal chemists. In contrast to most previous efforts aimed at breaking molecules using retrosynthetic feasible rules, our approach strives to preserve the functional groups, which may reveal the specific interaction pattern, e.g., the amide groups. Full article
(This article belongs to the Special Issue Molecular Structure and Simulation in Biological System)
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13 pages, 9534 KiB  
Article
Coarse-Grained MD Simulations of Opioid Interactions with the μ-Opioid Receptor and the Surrounding Lipid Membrane
by Sourav Ray, Konstantin Fackeldey, Christoph Stein and Marcus Weber
Biophysica 2023, 3(2), 263-275; https://doi.org/10.3390/biophysica3020017 - 06 Apr 2023
Viewed by 1230
Abstract
In our previous studies, a new opioid (NFEPP) was developed to only selectively bind to the μ-opoid receptor (MOR) in inflamed tissue and thus avoid the severe side effects of fentanyl. We know that NFEPP has a reduced binding affinity to MOR [...] Read more.
In our previous studies, a new opioid (NFEPP) was developed to only selectively bind to the μ-opoid receptor (MOR) in inflamed tissue and thus avoid the severe side effects of fentanyl. We know that NFEPP has a reduced binding affinity to MOR in healthy tissue. Inspired by the modelling and simulations performed by Sutcliffe et al., we present our own results of coarse-grained molecular dynamics simulations of fentanyl and NFEPP with regards to their interaction with the μ-opioid receptor embedded within the lipid cell membrane. For technical reasons, we have slightly modified Sutcliffe’s parametrisation of opioids. The pH-dependent opioid simulations are of interest because while fentanyl is protonated at the physiological pH, NFEPP is deprotonated due to its lower pKa value than that of fentanyl. Here, we analyse for the first time whether pH changes have an effect on the dynamical behaviour of NFEPP when it is inside the cell membrane. Besides these changes, our analysis shows a possible alternative interaction of NFEPP at pH 7.4 outside the binding region of the MOR. The interaction potential of NFEPP with MOR is also depicted by analysing the provided statistical molecular dynamics simulations with the aid of an eigenvector analysis of a transition rate matrix. In our modelling, we see differences in the XY-diffusion profiles of NFEPP compared with fentanyl in the cell membrane. Full article
(This article belongs to the Special Issue Molecular Structure and Simulation in Biological System)
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11 pages, 3709 KiB  
Article
Structural Analysis of Interactions between Epidermal Growth Factor Receptor (EGFR) Mutants and Their Inhibitors
by Yingzhe Guo, Zeqian Du and Ting Shi
Biophysica 2023, 3(1), 203-213; https://doi.org/10.3390/biophysica3010013 - 14 Mar 2023
Cited by 3 | Viewed by 1678
Abstract
People’s lives and health are gravely threatened by non-small-cell lung cancer (NSCLC). Mutations in epidermal growth factor receptor (EGFR), a transmembrane receptor tyrosine kinase, are considered one of the causes of NSCLC. Tyrosine kinase inhibitors (TKIs) are typically used to treat patients with [...] Read more.
People’s lives and health are gravely threatened by non-small-cell lung cancer (NSCLC). Mutations in epidermal growth factor receptor (EGFR), a transmembrane receptor tyrosine kinase, are considered one of the causes of NSCLC. Tyrosine kinase inhibitors (TKIs) are typically used to treat patients with EGFR mutations. In this study, Gefitinib, a member of the first generation of TKIs, was used to treat an EGFR single-point mutation (single mutant, SM). Patients harboring additional T790M mutations in the kinase domain of the EGFR were resistant to Gefitinib. Then, the L858R/T790M double mutation (double mutant, DM) was treated with the second generation of TKIs, such as Afatinib. Here, we constructed four computational models to uncover the structural basis between EGFR mutants (SM and DM) and corresponding inhibitors (Gefitinib and Afatinib). The binding energy in the G-SM (representing Gefitinib in complex with SM) system was larger than that in the G-DM (Representing Gefitinib in complex with DM) system. Gefitinib’s affinity with L792 and M793 was drastically reduced by the longer side chain of M790 in the G-DM system, which pushed Gefitinib outside of the pocket. Additionally, the A-DM system’s binding energy was higher than the G-DM system’s. Afatinib, unlike Gefitinib, induced the P-loop region to move downwards to decrease the pocket entrance size to accommodate Afatinib properly and stably in the A-DM (Afatinib in complex with DM) system. These results uncover the details of interactions between EGFR and its inhibitors and shed light on the design of new tyrosine kinase inhibitors. Full article
(This article belongs to the Special Issue Molecular Structure and Simulation in Biological System)
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19 pages, 5071 KiB  
Article
Insights into the Substrate Uptake Mechanism of Mycobacterium Tuberculosis Ribose 5-Phosphate Isomerase and Perspectives on Drug Development
by Leonardo Bartkevihi, Ícaro P. Caruso, Bruna Martins, José R. M. Pires, Danielle M. P. Oliveira, Cristiane Dinis Anobom and Fabio C. L. Almeida
Biophysica 2023, 3(1), 139-157; https://doi.org/10.3390/biophysica3010010 - 01 Mar 2023
Viewed by 1297
Abstract
The active site of the dimeric ribose 5-phosphate isomerase B (RpiB) contains a solvent-exposed barrier formed by residues H12, R113, R137, and R141, which is closed upon the complexation of phosphate. The substrate ribose 5-phosphate (R5P) has to overcome the surface barrier to [...] Read more.
The active site of the dimeric ribose 5-phosphate isomerase B (RpiB) contains a solvent-exposed barrier formed by residues H12, R113, R137, and R141, which is closed upon the complexation of phosphate. The substrate ribose 5-phosphate (R5P) has to overcome the surface barrier to reach an internal cavity and then bind in the linear configuration of ribose to the interface between the two subunits. NMR and molecular dynamics simulation are suitable methods to describe the transient nature of the RpiB active site and help our understanding of the mechanism of substrate entrance. In this study, we show that the entrance of the nucleotides AMP/ADP into the internal cavity of mycobacterium tuberculosis RpiB (MtRpiB) does not involve a canonical open/close-lid conformational transition usually observed in many enzymes. Instead, a flipping mechanism in which the nucleotide phosphate interacts with the surface barrier followed by the flip of the nitrogenous base and ribose is responsible for changing the substrate/ligand orientation from a solvent-exposed to a buried state. Based on these results, we propose a substrate/inhibitor uptake mechanism that could provide a basis for rational drug design using MtRpiB, which is an essential enzyme and a good target for drug development. Full article
(This article belongs to the Special Issue Molecular Structure and Simulation in Biological System)
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18 pages, 5761 KiB  
Article
Investigation of the Impact of Lipid Acyl Chain Saturation on Fusion Peptide Interactions with Lipid Bilayers
by William T. Heller and Piotr A. Zolnierczuk
Biophysica 2023, 3(1), 121-138; https://doi.org/10.3390/biophysica3010009 - 28 Feb 2023
Cited by 2 | Viewed by 1944
Abstract
The interaction of many peptides with lipid bilayer membranes strongly depends on the lipid composition. Here, a study of the impact of unsaturated lipid acyl chains on the interaction of a derivative of the HIV-1 fusion peptide with lipid bilayer vesicles is presented. [...] Read more.
The interaction of many peptides with lipid bilayer membranes strongly depends on the lipid composition. Here, a study of the impact of unsaturated lipid acyl chains on the interaction of a derivative of the HIV-1 fusion peptide with lipid bilayer vesicles is presented. Lipid bilayer vesicles composed of mixtures of lipids with two saturated acyl chains and lipids and one saturated and one unsaturated acyl chain, but identical head groups, were studied. The dependence of the peptide conformation on the unsaturated lipid content was probed by circular dichroism spectroscopy, while the impact of the peptide on the bilayer structure was determined by small-angle neutron scattering. The impact of the peptide on the lipid bilayer vesicle dynamics was investigated using neutron spin echo spectroscopy. Molecular dynamics simulations were used to characterize the behavior of the systems studied to determine if there were clear differences in their physical properties. The results reveal that the peptide–bilayer interaction is not a simple function of the unsaturated lipid acyl chain content of the bilayer. Instead, the peptide behavior is more consistent with that seen for the bilayer containing only unsaturated lipids, which is supported by lipid-specific interactions revealed by the simulations. Full article
(This article belongs to the Special Issue Molecular Structure and Simulation in Biological System)
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22 pages, 10971 KiB  
Article
Structural Insights into Plasticity and Discovery of Flavonoid Allosteric Inhibitors of Flavivirus NS2B–NS3 Protease
by Marielena Vogel Saivish, Gabriela de Lima Menezes, Vivaldo Gomes da Costa, Liliane Nebo, Gislaine Celestino Dutra da Silva, Carolina Colombelli Pacca, Rafael Elias Marques, Maurício Lacerda Nogueira and Roosevelt Alves Da Silva
Biophysica 2023, 3(1), 71-92; https://doi.org/10.3390/biophysica3010006 - 01 Feb 2023
Cited by 1 | Viewed by 2088
Abstract
Flaviviruses are among the most critical pathogens in tropical regions; they cause various severe diseases in developing countries but are not restricted to these countries. The development of antiviral therapeutics is crucial for managing flavivirus outbreaks. Ten proteins are encoded in the flavivirus [...] Read more.
Flaviviruses are among the most critical pathogens in tropical regions; they cause various severe diseases in developing countries but are not restricted to these countries. The development of antiviral therapeutics is crucial for managing flavivirus outbreaks. Ten proteins are encoded in the flavivirus RNA. The N2B–NS3pro protein complex plays a fundamental role in flavivirus replication and is a promising drug target; however, no flavivirus protease inhibitors have progressed to the preclinical stage. This study analyzed the structural models and plasticity of the NS2B–NS3pro protein complex of five medically important non-dengue flaviviruses (West Nile, Rocio, Ilhéus, yellow fever, and Saint Louis encephalitis). The flavonoids amentoflavone, tetrahydrorobustaflavone, and quercetin were selected for their exceptional binding energies as potential inhibitors of the NS2B–NS3pro protein complex. AutoDock Vina results ranged from −7.0 kcal/mol to −11.5 kcal/mol and the compounds preferentially acted non-competitively. Additionally, the first structural model for the NS2B–NS3pro protein complex was proposed for Ilhéus and Rocio viruses. The NS2B–NS3pro protease is an attractive molecular target for drug development. The three identified natural flavonoids showed great inhibitory potential against the viral species. Nevertheless, further in silico and in vitro studies are required to obtain more information regarding NS2B–NS3pro inhibition by these flavonoids and their therapeutic potential. Full article
(This article belongs to the Special Issue Molecular Structure and Simulation in Biological System)
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