SummaryMolecular dynamics (MD) determines the physical motions of atoms of a biological macromolecule in a cell-like environment and is an important method in structural bioinformatics. Traditionally, measurements such as root mean square deviation, root mean square fluctuation, radius of gyration, and various energy measures have been used to analyze MD simulations. Here, we present MD-TASK, a novel software suite that employs graph theory techniques, perturbation response scanning, and dynamic cross-correlation to provide unique ways for analyzing MD trajectories.Availability and implementationMD-TASK has been open-sourced and is available for download from https://github.com/RUBi-ZA/MD-TASK, implemented in Python and supported on Linux/Unix.

A new coronavirus (SARS-CoV-2) is a global threat to world health and economy. Its dimeric main protease (M pro ), which is required for the proteolytic cleavage of viral precursor proteins, is a good candidate for drug development owing to its conservation and the absence of a human homolog. Improving our understanding of M pro behavior can accelerate the discovery of effective therapies to reduce mortality. All-atom molecular dynamics (MD) simulations (100 ns) of 50 mutant M pro dimers obtained from filtered sequences from the GISAID database were analyzed using root-mean-square deviation, root-mean-square fluctuation, R g , averaged betweenness centrality, and geometry calculations. The results showed that SARS-CoV-2 M pro essentially behaves in a similar manner to its SAR-CoV homolog. However, we report the following new findings from the variants: (1) Residues GLY15, VAL157, and PRO184 have mutated more than once in SARS CoV-2; (2) the D48E variant has lead to a novel “TSEEMLN”” loop at the binding pocket; (3) inactive apo M pro does not show signs of dissociation in 100 ns MD; (4) a non-canonical pose for PHE140 widens the substrate binding surface; (5) dual allosteric pockets coinciding with various stabilizing and functional components of the substrate binding pocket were found to display correlated compaction dynamics; (6) high betweenness centrality values for residues 17 and 128 in all M pro samples suggest their high importance in dimer stability—one such consequence has been observed for the M17I mutation whereby one of the N-fingers was highly unstable. (7) Independent coarse-grained Monte Carlo simulations suggest a relationship between the rigidity/mutability and enzymatic function. Our entire approach combining database preparation, variant retrieval, homology modeling, dynamic residue network (DRN), relevant conformation retrieval from 1-D kernel density estimates from reaction coordinates to other existing approaches of structural analysis, and data visualization within the coronaviral M pro is also novel and is applicable to other coronaviral proteins.

Understanding molecular mechanisms underlying the complexity of allosteric regulation in proteins has attracted considerable attention in drug discovery due to the benefits and versatility of allosteric modulators in providing desirable selectivity against protein targets while minimizing toxicity and other side effects. The proliferation of novel computational approaches for predicting ligand–protein interactions and binding using dynamic and network-centric perspectives has led to new insights into allosteric mechanisms and facilitated computer-based discovery of allosteric drugs. Although no absolute method of experimental and in silico allosteric drug/site discovery exists, current methods are still being improved. As such, the critical analysis and integration of established approaches into robust, reproducible, and customizable computational pipelines with experimental feedback could make allosteric drug discovery more efficient and reliable. In this article, we review computational approaches for allosteric drug discovery and discuss how these tools can be utilized to develop consensus workflows for in silico identification of allosteric sites and modulators with some applications to pathogen resistance and precision medicine. The emerging realization that allosteric modulators can exploit distinct regulatory mechanisms and can provide access to targeted modulation of protein activities could open opportunities for probing biological processes and in silico design of drug combinations with improved therapeutic indices and a broad range of activities.

The Renin-Angiotensin System (RAS) plays an important role in regulating blood pressure and controlling sodium levels in the blood. Hyperactivity of this system has been linked to numerous conditions including hypertension, kidney disease, and congestive heart failure. As such, various classes of drugs have been developed to inhibit this system. These drugs are aimed at preventing angiotensin II from performing its function by inhibiting angiotensin II receptors or inhibiting angiotensin-converting enzyme from converting angiotensin I to angiotensin II. The last class of inhibitors is aimed at preventing angiotensin I from being formed by preventing renin from interacting with a plasma protein called angiotensinogen. In this study, we provide a structure-based analysis of the effect of single nucleotide variants on the interaction between renin and angiotensinogen with the aim of revealing important residues and potentially damaging variants.

Highlights Web server for MD-TASK and MODE-TASK, with new tools and updates. Eight dynamic residue network centrality metrics for analyzing protein molecular dynamics, extended for static proteins. Comparative essential dynamics for improved comparison of independent molecular dynamic simulations of related proteins. A communication propensity tool for evaluating residue communication efficiency. Normal mode analysis of proteins from static structures and molecular dynamic simulations.