Dataset Information

Reaction Pathway Sampling and Free-Energy Analyses for Multimeric Protein Complex Disassembly by Employing Hybrid Configuration Bias Monte Carlo/Molecular Dynamics Simulation.

ABSTRACT: Physicochemical characterization of multimeric biomacromolecule assembly and disassembly processes is a milestone to understand the mechanisms for biological phenomena at the molecular level. Mass spectroscopy (MS) and structural bioinformatics (SB) approaches have become feasible to identify subcomplexes involved in assembly and disassembly, while they cannot provide atomic information sufficient for free-energy calculation to characterize transition mechanism between two different sets of subcomplexes. To combine observations derived from MS and SB approaches with conventional free-energy calculation protocols, we here designed a new reaction pathway sampling method by employing hybrid configuration bias Monte Carlo/molecular dynamics (hcbMC/MD) scheme and applied it to simulate the disassembly process of serum amyloid P component (SAP) pentamer. The results we obtained are consistent with those of the earlier MS and SB studies with respect to SAP subcomplex species and the initial stage of SAP disassembly processes. Furthermore, we observed a novel dissociation event, ring-opening reaction of SAP pentamer. Employing free-energy calculation combined with the hcbMC/MD reaction pathway trajectories, we moreover obtained experimentally testable observations on (1) reaction time of the ring-opening reaction and (2) importance of Asp42 and Lys117 for stable formation of SAP oligomer.

SUBMITTER: Kurisaki I

PROVIDER: S-EPMC7905796 | biostudies-literature | 2021 Feb

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Reaction Pathway Sampling and Free-Energy Analyses for Multimeric Protein Complex Disassembly by Employing Hybrid Configuration Bias Monte Carlo/Molecular Dynamics Simulation.

Kurisaki Ikuo I Tanaka Shigenori S

ACS omega 20210205 7

Physicochemical characterization of multimeric biomacromolecule assembly and disassembly processes is a milestone to understand the mechanisms for biological phenomena at the molecular level. Mass spectroscopy (MS) and structural bioinformatics (SB) approaches have become feasible to identify subcomplexes involved in assembly and disassembly, while they cannot provide atomic information sufficient for free-energy calculation to characterize transition mechanism between two different sets of subc ...[more]

PMID: 33644582

Similar Datasets

Project description:ObjectivesProlonged intermittent renal replacement therapy is an increasingly popular treatment for acute kidney injury in critically ill patients that runs at different flow rates and durations than conventional hemodialysis or continuous renal replacement therapies. Pharmacokinetic studies conducted in patients receiving prolonged intermittent renal replacement therapy are scarce; consequently, clinicians are challenged to dose antibiotics effectively. The purpose of this study was to develop vancomycin dosing recommendations for patients receiving prolonged intermittent renal replacement therapy.MethodsMonte Carlo simulations were performed in thousands of virtual patients derived from previously published demographic, pharmacokinetic, and dialytic information derived from critically ill patients receiving vancomycin and other forms of renal replacement therapy. We conducted "in silico" vancomycin pharmacokinetic/pharmacodynamics analyses in these patients receiving prolonged intermittent renal replacement therapy to determine what vancomycin dose would achieve vancomycin 24-h area under the curve (AUC24h) of 400-700 mg·h/L, a target associated with positive clinical outcomes. Nine different vancomycin dosing regimens were tested using four different, commonly used prolonged intermittent renal replacement therapy modalities. A dosing nomogram based on serum concentration data achieved after the third dose was developed to individualize vancomycin therapy.ResultsAn initial vancomycin dose of 15 or 20 mg/kg immediately followed by 15 mg/kg after subsequent prolonged intermittent renal replacement therapy treatments achieved AUC24h of ≥400 mg·h/L for ≥90% of patients regardless of prolonged intermittent renal replacement therapy duration, modality, or time of vancomycin dose relative to prolonged intermittent renal replacement therapy. Many patients experienced AUC24h of ≥700 mg·h/L, but once the dosing nomogram was applied to serum concentrations obtained after the third vancomycin dose, 67%-88% of patients achieved AUC24h of 400-700 mg·h/L.ConclusionAn initial loading dose of 15-20 mg/kg followed by a maintenance regimen of 15 mg/kg after every prolonged intermittent renal replacement therapy session coupled with serum concentration monitoring should be used to individualize vancomycin dosing. These predictions need clinical verification.

Dataset Information

Reaction Pathway Sampling and Free-Energy Analyses for Multimeric Protein Complex Disassembly by Employing Hybrid Configuration Bias Monte Carlo/Molecular Dynamics Simulation.

Publications

Reaction Pathway Sampling and Free-Energy Analyses for Multimeric Protein Complex Disassembly by Employing Hybrid Configuration Bias Monte Carlo/Molecular Dynamics Simulation.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets