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Applications of Computational Modeling in Disease, Infection and Drug Design

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Biophysics".

Deadline for manuscript submissions: closed (31 December 2021) | Viewed by 12396

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Dr. Paulino Gómez-Puertas

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Molecular Modelling Group, Center of Molecular Biology “Severo Ochoa” (CSIC-UAM), Cantoblanco, E-28049 Madrid, Spain
Interests: computational biology; drug design; molecular biology; molecular dynamics; genetics disorders
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Dear Colleagues,

Simulation techniques using computational biology, including molecular modeling, molecular dynamics, ligand docking or drug screening, allow rationalization at the molecular level of the causes of different diseases. Using these virtual modeling techniques, it is possible to understand why a variant in an amino acid causes the failure of an enzyme or a group of macromolecules in the case of diseases of genetic origin. Likewise, the interactions between viral proteins and different target proteins in the host cell can be modeled, as well as the design of new antiviral compounds. It is also possible to simulate the functioning of bacterial proteins responsible for their pathogenicity in detail. In the latter case, antibiotic-resistant bacteria have become a major cause of mortality and morbidity and the main threat in hospital- and community-acquired infections. Among the ways to address antibiotic resistance, the use of computer-designed new drugs and therapies appears as the most innovative.

In this Special Issue, we welcome papers using virtual modeling techniques in computational biology, alone or in combination with in vitro or in vivo strategies, for the characterization and therapy of diseases, whether of genetic origin, or viral or bacterial infections, including the design of new drugs and therapies.

Dr. Paulino Gómez-Puertas
Guest Editor

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Keywords

computational biology
drug design
molecular dynamics
genetic diseases
virus infection
antimicrobials
antibiotic resistance

Published Papers (6 papers)

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Research

16 pages, 9130 KiB

Open AccessArticle

Effect of Single-Residue Mutations on CTCF Binding to DNA: Insights from Molecular Dynamics Simulations

by Albert Mao, Carrie Chen, Stephanie Portillo-Ledesma and Tamar Schlick

Int. J. Mol. Sci. 2023, 24(7), 6395; https://doi.org/10.3390/ijms24076395 - 29 Mar 2023

Viewed by 1914

Abstract

In humans and other eukaryotes, DNA is condensed into chromatin fibers that are further wound into chromosomes. This organization allows regulatory elements in the genome, often distant from each other in the linear DNA, to interact and facilitate gene expression through regions known as topologically associating domains (TADs). CCCTC–binding factor (CTCF) is one of the major components of TAD formation and is responsible for recruiting a partner protein, cohesin, to perform loop extrusion and facilitate proper gene expression within TADs. Because single-residue CTCF mutations have been linked to the development of a variety of cancers in humans, we aim to better understand how these mutations affect the CTCF structure and its interaction with DNA. To this end, we compare all-atom molecular dynamics simulations of a wildtype CTCF–DNA complex to those of eight different cancer-linked CTCF mutant sequences. We find that most mutants have lower binding energies compared to the wildtype protein, leading to the formation of less stable complexes. Depending on the type and position of the mutation, this loss of stability can be attributed to major changes in the electrostatic potential, loss of hydrogen bonds between the CTCF and DNA, and/or destabilization of specific zinc fingers. Interestingly, certain mutations in specific fingers can affect the interaction with the DNA of other fingers, explaining why mere single mutations can impair CTCF function. Overall, these results shed mechanistic insights into experimental observations and further underscore CTCF’s importance in the regulation of chromatin architecture and gene expression. Full article

(This article belongs to the Special Issue Applications of Computational Modeling in Disease, Infection and Drug Design)

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29 pages, 4983 KiB

Open AccessArticle

Allosteric Determinants of the SARS-CoV-2 Spike Protein Binding with Nanobodies: Examining Mechanisms of Mutational Escape and Sensitivity of the Omicron Variant

by Gennady Verkhivker

Int. J. Mol. Sci. 2022, 23(4), 2172; https://doi.org/10.3390/ijms23042172 - 16 Feb 2022

Cited by 5 | Viewed by 2099

Abstract

Structural and biochemical studies have recently revealed a range of rationally engineered nanobodies with efficient neutralizing capacity against the SARS-CoV-2 virus and resilience against mutational escape. In this study, we performed a comprehensive computational analysis of the SARS-CoV-2 spike trimer complexes with single nanobodies Nb6, VHH E, and complex with VHH E/VHH V nanobody combination. We combined coarse-grained and all-atom molecular simulations and collective dynamics analysis with binding free energy scanning, perturbation-response scanning, and network centrality analysis to examine mechanisms of nanobody-induced allosteric modulation and cooperativity in the SARS-CoV-2 spike trimer complexes with these nanobodies. By quantifying energetic and allosteric determinants of the SARS-CoV-2 spike protein binding with nanobodies, we also examined nanobody-induced modulation of escaping mutations and the effect of the Omicron variant on nanobody binding. The mutational scanning analysis supported the notion that E484A mutation can have a significant detrimental effect on nanobody binding and result in Omicron-induced escape from nanobody neutralization. Our findings showed that SARS-CoV-2 spike protein might exploit the plasticity of specific allosteric hotspots to generate escape mutants that alter response to binding without compromising activity. The network analysis supported these findings showing that VHH E/VHH V nanobody binding can induce long-range couplings between the cryptic binding epitope and ACE2-binding site through a broader ensemble of communication paths that is less dependent on specific mediating centers and therefore may be less sensitive to mutational perturbations of functional residues. The results suggest that binding affinity and long-range communications of the SARS-CoV-2 complexes with nanobodies can be determined by structurally stable regulatory centers and conformationally adaptable hotspots that are allosterically coupled and collectively control resilience to mutational escape. Full article

(This article belongs to the Special Issue Applications of Computational Modeling in Disease, Infection and Drug Design)

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16 pages, 3763 KiB

Open AccessArticle

Influenza A Virus NS1 Protein Structural Flexibility Analysis According to Its Structural Polymorphism Using Computational Approaches

by Sarah Naceri, Daniel Marc, Anne-Claude Camproux and Delphine Flatters

Int. J. Mol. Sci. 2022, 23(3), 1805; https://doi.org/10.3390/ijms23031805 - 04 Feb 2022

Cited by 2 | Viewed by 1885

Abstract

Influenza A viruses are highly contagious RNA viruses that cause respiratory tract infections in humans and animals. Their non-structural protein NS1, a homodimer of two 230-residue chains, is the main viral factor in counteracting the antiviral defenses of the host cell. Its RNA-binding domain is an obligate dimer that is connected to each of the two effector domains by a highly flexible unstructured linker region of ten amino acids. The flexibility of NS1 is a key property that allows its effector domains and its RNA binding domain to interact with several protein partners or RNAs. The three-dimensional structures of full-length NS1 dimers revealed that the effector domains could adopt three distinct conformations as regards their mutual interactions and their orientation relative to the RNA binding domain (closed, semi-open and open). The origin of this structural polymorphism is currently being investigated and several hypotheses are proposed, among which one posits that it is a strain-specific property. In the present study, we explored through computational molecular modeling the dynamic and flexibility properties of NS1 from three important influenza virus A strains belonging to three distinct subtypes (H1N1, H6N6, H5N1), for which at least one conformation is available in the Protein Data Bank. In order to verify whether NS1 is stable in three forms for the three strains, we constructed homology models if the corresponding forms were not available in the Protein Data Bank. Molecular dynamics simulations were performed in order to predict the stability over time of the three distinct sequence variants of NS1, in each of their three distinct conformations. Our results favor the co-existence of three stable structural forms, regardless of the strain, but also suggest that the length of the linker, along with the presence of specific amino acids, modulate the dynamic properties and the flexibility of NS1. Full article

(This article belongs to the Special Issue Applications of Computational Modeling in Disease, Infection and Drug Design)

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18 pages, 46763 KiB

Open AccessArticle

Exploring the Structural Rearrangements of the Human Insulin-Degrading Enzyme through Molecular Dynamics Simulations

by Mariem Ghoula, Nathalie Janel, Anne-Claude Camproux and Gautier Moroy

Int. J. Mol. Sci. 2022, 23(3), 1746; https://doi.org/10.3390/ijms23031746 - 03 Feb 2022

Cited by 5 | Viewed by 2158

Abstract

Insulin-degrading enzyme (IDE) is a ubiquitously expressed metallopeptidase that degrades insulin and a large panel of amyloidogenic peptides. IDE is thought to be a potential therapeutic target for type-2 diabetes and neurodegenerative diseases, such as Alzheimer’s disease. IDE catalytic chamber, known as a crypt, is formed, so that peptides can be enclosed and degraded. However, the molecular mechanism of the IDE function and peptide recognition, as well as its conformation changes, remains elusive. Our study elucidates IDE structural changes and explains how IDE conformational dynamics is important to modulate the catalytic cycle of IDE. In this aim, a free-substrate IDE crystallographic structure (PDB ID: 2JG4) was used to model a complete structure of IDE. IDE stability and flexibility were studied through molecular dynamics (MD) simulations to witness IDE conformational dynamics switching from a closed to an open state. The description of IDE structural changes was achieved by analysis of the cavity and its expansion over time. Moreover, the quasi-harmonic analysis of the hinge connecting IDE domains and the angles formed over the simulations gave more insights into IDE shifts. Overall, our results could guide toward the use of different approaches to study IDE with different substrates and inhibitors, while taking into account the conformational states resolved in our study. Full article

(This article belongs to the Special Issue Applications of Computational Modeling in Disease, Infection and Drug Design)

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13 pages, 698 KiB

Open AccessArticle

Chemical Exposures Affect Innate Immune Response to SARS-CoV-2

by Olatunbosun Arowolo, Leonid Pobezinsky and Alexander Suvorov

Int. J. Mol. Sci. 2021, 22(22), 12474; https://doi.org/10.3390/ijms222212474 - 19 Nov 2021

Cited by 3 | Viewed by 1781

Abstract

Severe outcomes of COVID-19 are associated with pathological response of the immune system to the SARS-CoV-2 infection. Emerging evidence suggests that an interaction may exist between COVID-19 pathogenesis and a broad range of xenobiotics, resulting in significant increases in death rates in highly exposed populations. Therefore, a better understanding of the molecular basis of the interaction between SARS-CoV-2 infection and chemical exposures may open opportunities for better preventive and therapeutic interventions. We attempted to gain mechanistic knowledge on the interaction between SARS-CoV-2 infection and chemical exposures using an in silico approach, where we identified genes and molecular pathways affected by both chemical exposures and SARS-CoV-2 in human immune cells (T-cells, B-cells, NK-cells, dendritic, and monocyte cells). Our findings demonstrate for the first time that overlapping molecular mechanisms affected by a broad range of chemical exposures and COVID-19 are linked to IFN type I/II signaling pathways and the process of antigen presentation. Based on our data, we also predict that exposures to various chemical compounds will predominantly impact the population of monocytes during the response against COVID-19. Full article

(This article belongs to the Special Issue Applications of Computational Modeling in Disease, Infection and Drug Design)

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11 pages, 4923 KiB

Open AccessArticle

Evaluation of the Binding Mechanism of Human Defensin 5 in a Bacterial Membrane: A Simulation Study

by Tadsanee Awang, Phoom Chairatana, Ranjit Vijayan and Prapasiri Pongprayoon

Int. J. Mol. Sci. 2021, 22(22), 12401; https://doi.org/10.3390/ijms222212401 - 17 Nov 2021

Cited by 6 | Viewed by 1717

Abstract

Human α-defensin 5 (HD5) is a host-defense peptide exhibiting broad-spectrum antimicrobial activity. The lipopolysaccharide (LPS) layer on the Gram-negative bacterial membrane acts as a barrier to HD5 insertion. Therefore, the pore formation and binding mechanism remain unclear. Here, the binding mechanisms at five positions along the bacterial membrane axis were investigated using Molecular Dynamics. (MD) simulations. We found that HD5 initially placed at positions 1 to 3 moved up to the surface, while HD5 positioned at 4 and 5 remained within the membrane interacting with the middle and inner leaflet of the membrane, respectively. The arginines were key components for tighter binding with 3-deoxy-d-manno-octulosonic acid (KDO), phosphates of the outer and inner leaflets. KDO appeared to retard the HD5 penetration. Full article

(This article belongs to the Special Issue Applications of Computational Modeling in Disease, Infection and Drug Design)

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