Canonized then Minimized RMSD for Three-Dimensional Structures

Existing molecular canonization algorithms typically operate on one-dimensional (1D) string representations or two-dimensional (2D) connectivity graphs of a molecule and are not able to differentiate equivalent atoms based on three-dimensional (3D) structures. The stereochemical tags on each atom are in fact determined according to established Cahn-Ingold-Prelog (CIP) rules for comparing grades, which can help to further differentiate atoms with similar environment. Therefore, a stereochemical-rule-based canonization algorithm that is capable of assigning canonical indices using 3D structural information is of great value. On top of the Schneider-Sayle-Landrum (SSL) partition-based canonization algorithm, we propose an enhanced canonization algorithm to expand its applicability. The initial index assignment rules are redesigned, so that the obtained canonical indices are compatible with the most of the common CIP Sequence Rules, which greatly eases the stereochemical assignment. Furthermore, a branching tiebreaking step is added to secure an accurate evaluation of the structural difference through the minimized root-mean-square deviation (RMSD) between structures, with an option to include hydrogen atoms or not. Our algorithm is implemented with Python and can efficiently obtain minimized RMSD taking into account of the symmetry of molecular systems , contributing to the fields of drug design, molecular docking, and data analysis of molecular dynamics simulation

A mutational analysis and molecular dynamics simulation of quinolone resistance proteins QnrA1 and QnrC from Proteus mirabilis

<p>Abstract</p> <p>Background</p> <p>The first report on the transferable, plasmid-mediated quinolone-resistance determinant <it>qnrA1 </it>was in 1998. Since then, <it>qnr </it>alleles have been discovered worldwide in clinical strains of Gram-negative bacilli. Qnr proteins confer quinolone resistance, and belong to the pentapeptide repeat protein (PRP) family. Several PRP crystal structures have been solved, but little is known about the functional significance of their structural arrangement.</p> <p>Results</p> <p>We conducted random and site-directed mutagenesis on <it>qnrA1 </it>and on <it>qnrC</it>, a newly identified quinolone-resistance gene from <it>Proteus mirabilis</it>. Many of the Qnr mutants lost their quinolone resistance function. The highly conserved hydrophobic Leu or Phe residues at the center of the pentapeptide repeats are known as <it>i </it>sites, and loss-of-function mutations included replacement of the <it>i </it>site hydrophobic residues with charged residues, replacing the <it>i</it>^-2site, N-terminal to the <it>i </it>residues, with bulky side-chain residues, introducing Pro into the β-helix coil, deletion of the N- and C-termini, and excision of a central coil. Molecular dynamics simulations and homology modeling demonstrated that QnrC overall adopts a stable β-helix fold and shares more similarities with MfpA than with other PRP structures. Based on homology modeling and molecular dynamics simulation, the dysfunctional point mutations introduced structural deformations into the quadrilateral β-helix structure of PRPs. Of the pentapeptides of QnrC, two-thirds adopted a type II β-turn, while the rest adopted type IV turns. A gap exists between coil 2 and coil 3 in the QnrC model structure, introducing a structural flexibility that is similar to that seen in MfpA.</p> <p>Conclusion</p> <p>The hydrophobic core and the β-helix backbone conformation are important for maintaining the quinolone resistance property of Qnr proteins. QnrC may share structural similarity with MfpA.</p

Detailed Regulatory Mechanism of the Interaction between ZO-1 PDZ2 and Connexin43 Revealed by MD Simulations

The gap junction protein connexin43 (Cx43) binds to the second PDZ domain of Zonula occludens-1 (ZO-1) through its C-terminal tail, mediating the regulation of gap junction plaque size and dynamics. Biochemical study demonstrated that the very C-terminal 12 residues of Cx43 are necessary and sufficient for ZO-1 PDZ2 binding and phosphorylation at residues Ser (-9) and Ser (-10) of the peptide can disrupt the association. However, only a crystal structure of ZO-1 PDZ2 in complex with a shorter 9 aa peptide of connexin43 was solved experimentally. Here, the interactions between ZO-1 PDZ2 and the short, long and phosphorylated Cx43 peptides were studied using molecular dynamics (MD) simulations and free energy calculation. The short peptide bound to PDZ2 exhibits large structural variations, while the extension of three upstream residues stabilizes the peptide conformation and enhanced the interaction. Phosphorylation at Ser(-9) significantly weakens the binding and results in conformational flexibility of the peptide. Glu210 of ZO-1 PDZ2 was found to be a key regulatory point in Cx43 binding and phosphorylation induced dissociation

Fuzheng Jiedu granules against disease progression among high-risk adults with non-severe COVID-19: a multicenter retrospective cohort study

BackgroundFuzheng Jiedu (FZJD) granules are widely used to treat coronavirus disease (COVID-19) since their market approval, but their clinical effectiveness remains uncertain. In this study, we aimed to evaluate the effectiveness of FZJD in reducing disease progression in high-risk adults with COVID-19.MethodsA multicenter, retrospective cohort study involving high-risk adults with non-severe COVID-19 was conducted in China from May 2021 to December 2022. The study was registered at the Chinese Clinical Trial Registry (ChiCTR2200058097; https://www.chictr.org.cn/bin/project/edit?pid=160010). Patients were categorized into two groups based on the administration of FZJD granules. The outcomes included disease progression, mechanical ventilation, intensive care unit (ICU) admission, and mortality. Propensity-score analyses and multivariable regression were performed to assess the effectiveness of FZJD granules. The effectiveness was further analyzed in different subgroups.ResultsA total of 1,644 patients (54.7% female patients; mean age, 62.3 years) were included, with 27.4% (451/1,644) receiving FZJD granules. After propensity score matching (PSM), 320 FZJD granule receivers and 320 non-receivers were matched. Those receiving FZJD granules were associated with lower risks of disease progression [adjusted odds ratio (OR), 0.21; 95% confidence interval (CI), 0.06–0.73], mechanical ventilation (OR, 0.15; 95% CI, 0.03–0.66), and ICU admission (OR, 0.08; 95% CI, 0.01–0.64) than those not receiving FZJD granules. The lower risk of disease progression in the FZJD group was confirmed by multivariable regression analysis and various propensity-score analyses. Furthermore, subgroup analyses demonstrated significant treatment benefits in patients with moderate COVID-19 at admission (no progression to severe disease) or in those who were not fully vaccinated (OR, 0.06; 95% CI, 0.01–0.50).ConclusionFZJD administration was significantly associated with a reduced risk of disease progression in high-risk adults with mild-to-moderate COVID-19

The Conformational Transition Pathways of ATP-Binding Cassette Transporter BtuCD Revealed by Targeted Molecular Dynamics Simulation

BtuCD is a member of the ATP-binding cassette transporters in Escherichia coli that imports vitamin B12 into the cell by utilizing the energy of ATP hydrolysis. Crystal structures of BtuCD and its homologous protein HI1470/1 in various conformational states support the ‘‘alternating access’ ’ mechanism which proposes the conformational transitions of the substrate translocation pathway at transmembrane domain (TMD) between the outward-facing and inward-facing states. The conformational transition at TMD is assumed to couple with the movement of the cytoplasmic nucleotide-binding domains (NBDs) driven by ATP hydrolysis/binding. In this study, we performed targeted molecular dynamics (MD) simulations to explore the atomic details of the conformational transitions of BtuCD importer. The outward-facing to inward-facing (ORI) transition was found to be initiated by the conformational movement of NBDs. The subsequent reorientation of the substrate translocation pathway at TMD began with the closing of the periplasmic gate, followed by the opening of the cytoplamic gate in the last stage of the conformational transition due to the extensive hydrophobic interactions at this region, consistent with the functional requirement of unidirectional transport of the substrates. The reverse inward-facing to outward-facing (IRO) transition was found to exhibit intrinsic diversity of the conformational transition pathways and significant structural asymmetry, suggesting that the asymmetric crystal structure of BtuCD-F is a