Resistance against various antibiotics is being reported due to their excessive use to prevent secondary infection in COVID-19 patients

Resistance against various antibiotics is being reported due to their excessive use to prevent secondary infection in COVID-19 patients. and prioritize drug targets and new chemical entities, and to repurpose drugs. Here, we discuss how MD simulation has been explored by the scientific community to accelerate and guide translational research on SARS-CoV-2 in the past year. We have also considered future research directions for researchers, where MD simulations can help fill the existing gaps in COVID-19 research. 1.?Introduction Molecular dynamics (MD) simulation is a numerical method to study many-particle systems, such as molecules, clusters, and even macroscopic systems like gases, liquids, and solids. Broadly, it is a form of computer simulation in which atoms and molecules are allowed to interact for a fixed time period, which typically solves the classical equations of motion for atoms and molecules and obtains the time evolution information on a system. The initial grand success of MD simulation in material science and chemical physics paved the way for a broad yet unexplored field of biological sciences.1 It represents an interface between wet- and dry-lab and, therefore, is often described as a virtual microscope with high temporal and spatial resolution. MD simulation provides complete knowledge of a studied system, where if all trajectories are known, the thermodynamic, dynamic, and physicochemical properties of the molecules can be extracted and analyzed. As biological macromolecules exert their functions due to their dynamic rather than static nature, MD simulation serves as an ideal approach to investigate the range of accessible configurations and conformations of biomolecules as a function of time by the simultaneous integration of Newtons equations of motion.2 Over the past decades, MD simulations have been utilized in numerous studies, starting from understanding biomolecular structureCdynamicsCfunction relationships, conformational dynamics, allostery, drug design, and structure prediction refinement, to understanding disease pathophysiologies by mimicking physiological conditions and generating experimentally testable hypotheses and predictions (Physique ?Physique11).3?6 Inevitably, performing biochemical experiments on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is time-consuming and requires sophisticated safety protocols. In comparison, the computational studies are quick and easily performed and provide information that is sometimes challenging to obtain from the wet-lab experiments.7 Thus, MD simulation has emerged as the most common yet obvious method to investigate biomolecular interactions and conformational dynamics. Multiscale coarse-grained models have been used to understand the behavior of the complete SARS-CoV-2 virion.8 The experimentally decided high-resolution 3-D structures of SARS-CoV-2 proteins have been used for simulation studies to determine their detailed mechanistic attributes and dynamics and identify conformational changes. The combination of docking and MD simulation-based binding free energy calculations has proven valuable in understanding proteinCprotein conversation and identifying potential inhibitors. In addition, the MD studies have revealed crucial information on virusChost interactions. All of this information has helped accelerate COVID-19 research and has improved our knowledge of SARS-CoV-2 biology. In this Perspective, we discuss how MD simulation has been utilized to address various aspects of SARS-CoV-2-induced pathogenesis, with the specific intent being to help fill the gaps in our understanding of the new disease. Open in a separate window Physique 1 MD simulation system for the SARS-CoV-2 Mpro. A simulation box with two monomers TCS 401 free base of the Mpro dimer (PDB ID: 6LU7) is usually shown in blue and purple cartoons. Water is usually shown as transparent, and ions K+ and ClC are shown in tan and cyan van der Waals spheres, respectively. Reproduced with permission from ref (71). Copyright 2020 APOD American Chemical Society. 2.?Protein Interactions and Conformational Dynamics Perhaps the most crucial application of MD simulations in COVID-19 research has been its ability to reveal the structural dynamics and conformational arrangements of the viral proteins and associated proteinCprotein interactions. MD simulations have been instrumental in studying the structure, TCS 401 free base flexibility, packing, and interactions of SARS-CoV-2 proteins. In this section, we discuss the use of MD simulations for TCS 401 free base obtaining information for the dynamics and structure of viral proteins. 2.1. Spike Glycoprotein Spike glycoprotein (S-protein), one of the most prominent constructions of SARS-CoV-2, exists on the top of disease envelope and assists with attaching to the prospective cell receptor, particularly the angiotensin-converting enzyme 2 (ACE2) receptor. The S-protein can be club-shaped and is present like a trimer, with each monomer comprising two domains (S1 and S2). It really is heavily glycosylated using the N-linked and O-linked glycans also. As the S2-domain is.

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