Signal Propagation in the ATPase Domain of Mycobacterium tuberculosis DNA Gyrase from Dynamical-Nonequilibrium Molecular Dynamics Simulations.

DNA gyrases catalyze negative supercoiling of DNA, are essential for bacterial DNA replication, transcription, and recombination, and are important antibacterial targets in multiple pathogens, including Mycobacterium tuberculosis, which in 2021 caused >1.5 million deaths worldwide. DNA gyrase is a tetrameric (A2B2) protein formed from two subunit types: gyrase A (GyrA) carries the breakage-reunion active site, whereas gyrase B (GyrB) catalyzes ATP hydrolysis required for energy transduction and DNA translocation. The GyrB ATPase domains dimerize in the presence of ATP to trap the translocated DNA (T-DNA) segment as a first step in strand passage, for which hydrolysis of one of the two ATPs and release of the resulting inorganic phosphate is rate-limiting. Here, dynamical-nonequilibrium molecular dynamics (D-NEMD) simulations of the dimeric 43 kDa N-terminal fragment of M. tuberculosis GyrB show how events at the ATPase site (dissociation/hydrolysis of bound nucleotides) are propagated through communication pathways to other functionally important regions of the GyrB ATPase domain. Specifically, our simulations identify two distinct pathways that respectively connect the GyrB ATPase site to the corynebacteria-specific C-loop, thought to interact with GyrA prior to DNA capture, and to the C-terminus of the GyrB transduction domain, which in turn contacts the C-terminal GyrB topoisomerase-primase (TOPRIM) domain responsible for interactions with GyrA and the centrally bound G-segment DNA. The connection between the ATPase site and the C-loop of dimeric GyrB is consistent with the unusual properties of M. tuberculosis DNA gyrase relative to those from other bacterial species.

Structural analysis of the coronavirus main protease for the design of pan-variant inhibitors.

With the rapid rate of SARS-CoV-2 Main protease (Mpro) structures deposition, a computational method that can combine all the useful structural features becomes crucial. This research focuses on the frequently occurring atoms and residues to find a generalized strategy for inhibitor design given a large amount of protein complexes from SARS-CoV in contrast to SARS-CoV-2 Mpro. By superposing large numbers of the ligands onto the protein template and grid box, we can analyse which part of the structure is conserved from position-specific interaction for both data sets for the development of pan-Mpro antiviral design. The difference in conserved recognition sites from the crystal structures can be used to determine specificity determining residues for designing selective drugs. We can display pictures of the imaginary shape of the ligand by unionising all atoms from the ligand. We also pinpoint the most probable atom adjustments to imitate the frequently found densities from the ligand atoms statistics. With molecular docking, Molecular Dynamics simulation, and MM-PBSA methods, a carbonyl replacement at the nitrile warhead (N5) of Paxlovid's Nirmatrelvir (PF-07321332) was suggested. By gaining insights into the selectivity and promiscuity regions for proteins and ligands, crucial residues are highlighted, and the antiviral design strategies are proposed.

Adsorption study of lac dyes with chitosan coated on silk fibroin using molecular dynamics simulations.

Silk is a protein polymer composed of the polypeptide chains including the repeating units of glycine and alanine. Lac dye is composed mainly of two major anthraquinone based components: laccaic acids A and B. Previously, chitosan was reported and used to coat silk in the lac dyeing process for enhancing the uptake of lac dye on silk. Therefore, this work aims to explain why chitosan can help in lac dyeing process on silk by using molecular docking and molecular dynamics (MD) simulations. The molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) analysis was also applied to calculate the binding free energy. The results revealed the attractive interaction between silk and chitosan. Moreover, an increasing unit of acetylglucosamine in the chitosan structure increases the binding interaction between silk and chitosan. After that, the binding between silk complexed with chitosan and laccaic acids A and B were reported. It was clearly found that the average of binding free energies between lac dyes and silk complexed with chitosan (-257.7 and -230.9 kJ/mol) was lower than those between lac dyes and silk without chitosan (-13.4 and -108.5 kJ/mol) indicating the better binding of lac dyes when chitosan is added on the silk surface. The obtained results can be explained why the existence of chitosan on silk surface could increase the binding of lac dyes. Therefore, this study can be used as a guideline in order to understand and improve the fastness properties of textiles.