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Computational Simulation of Macromolecular Processes Involved in Disease

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 (30 April 2024) | Viewed by 943

Special Issue Editor

Special Issue Information

Dear Colleagues,

The structural information of macromolecules is of great importance for understanding the mechanisms underlying various types of diseases.

This atomic-scale information allows a precise understanding of the mechanisms underlying different types of biological systems, as well as techniques capable of computationally simulating the movement of these macromolecules in their biological environment, helping us to rationalize mechanisms and understand how biological systems operate, including intermolecular interactions, intracellular interactions, etc.

In addition, computational drug design relies on knowledge of the active sites or allosteric sites of enzymes to find chemical compounds that can stably bind to the amino acids present in them, thus inhibiting or modulating their activity.

This Special Issue welcomes contributions that use three-dimensional molecular structure techniques and/or virtual modeling in computational biology, alone or in combination with in vitro or in vivo strategies. The goal of these techniques may be disease prevention, discovery, characterization, or therapy. 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 systems are also welcome.

Dr. Paulino Gómez-Puertas
Guest Editor

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Keywords

  • computational biology
  • virtual modeling
  • drug discovery
  • molecular dynamics
  • molecular mechanism of disease

Published Papers (1 paper)

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Research

28 pages, 4619 KiB  
Article
Ensemble-Based Mutational Profiling and Network Analysis of the SARS-CoV-2 Spike Omicron XBB Lineages for Interactions with the ACE2 Receptor and Antibodies: Cooperation of Binding Hotspots in Mediating Epistatic Couplings Underlies Binding Mechanism and Immune Escape
by Nishank Raisinghani, Mohammed Alshahrani, Grace Gupta and Gennady Verkhivker
Int. J. Mol. Sci. 2024, 25(8), 4281; https://doi.org/10.3390/ijms25084281 - 12 Apr 2024
Viewed by 637
Abstract
In this study, we performed a computational study of binding mechanisms for the SARS-CoV-2 spike Omicron XBB lineages with the host cell receptor ACE2 and a panel of diverse class one antibodies. The central objective of this investigation was to examine the molecular [...] Read more.
In this study, we performed a computational study of binding mechanisms for the SARS-CoV-2 spike Omicron XBB lineages with the host cell receptor ACE2 and a panel of diverse class one antibodies. The central objective of this investigation was to examine the molecular factors underlying epistatic couplings among convergent evolution hotspots that enable optimal balancing of ACE2 binding and antibody evasion for Omicron variants BA.1, BA2, BA.3, BA.4/BA.5, BQ.1.1, XBB.1, XBB.1.5, and XBB.1.5 + L455F/F456L. By combining evolutionary analysis, molecular dynamics simulations, and ensemble-based mutational scanning of spike protein residues in complexes with ACE2, we identified structural stability and binding affinity hotspots that are consistent with the results of biochemical studies. In agreement with the results of deep mutational scanning experiments, our quantitative analysis correctly reproduced strong and variant-specific epistatic effects in the XBB.1.5 and BA.2 variants. It was shown that Y453W and F456L mutations can enhance ACE2 binding when coupled with Q493 in XBB.1.5, while these mutations become destabilized when coupled with the R493 position in the BA.2 variant. The results provided a molecular rationale of the epistatic mechanism in Omicron variants, showing a central role of the Q493/R493 hotspot in modulating epistatic couplings between convergent mutational sites L455F and F456L in XBB lineages. The results of mutational scanning and binding analysis of the Omicron XBB spike variants with ACE2 receptors and a panel of class one antibodies provide a quantitative rationale for the experimental evidence that epistatic interactions of the physically proximal binding hotspots Y501, R498, Q493, L455F, and F456L can determine strong ACE2 binding, while convergent mutational sites F456L and F486P are instrumental in mediating broad antibody resistance. The study supports a mechanism in which the impact on ACE2 binding affinity is mediated through a small group of universal binding hotspots, while the effect of immune evasion could be more variant-dependent and modulated by convergent mutational sites in the conformationally adaptable spike regions. Full article
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