2017
DOI: 10.1002/jcc.24845
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Efficient estimation of binding free energies between peptides and an MHC class II molecule using coarse‐grained molecular dynamics simulations with a weighted histogram analysis method

Abstract: We estimate the binding free energy between peptides and an MHC class II molecule using molecular dynamics (MD) simulations with the weighted histogram analysis method (WHAM). We show that, owing to its more thorough sampling in the available computational time, the binding free energy obtained by pulling the whole peptide using a coarse-grained (CG) force field (MARTINI) is less prone to significant error induced by inadequate-sampling than using an atomistic force field (AMBER). We further demonstrate that u… Show more

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Cited by 16 publications
(14 citation statements)
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“…In addition, the differences of Δ W PMF values for NMS-P715 between WT and C604Y mutation were much larger than those for Cpd-5 (9D and 10D). Previous studies proposed that the higher the PMF curve, the more free energy was released during the ligand dissociate from the target, thus longer residence time [ 30 ]. In other words, the C604Y mutation could induce resistance to both Cpd-5 and NMS-P715, but exhibited only slight impact on reversine.…”
Section: Resultsmentioning
confidence: 99%
“…In addition, the differences of Δ W PMF values for NMS-P715 between WT and C604Y mutation were much larger than those for Cpd-5 (9D and 10D). Previous studies proposed that the higher the PMF curve, the more free energy was released during the ligand dissociate from the target, thus longer residence time [ 30 ]. In other words, the C604Y mutation could induce resistance to both Cpd-5 and NMS-P715, but exhibited only slight impact on reversine.…”
Section: Resultsmentioning
confidence: 99%
“…The related approaches of targeted MD (TMD) and umbrella sampling apply forces in order to promote new conformations, and are used to predict a pathway between two known conformations. Such “pulling” simulations, although not used to study dynamics per se , have been used to estimate the binding free energies between peptides and MHC (59). The atomic complexity of the system can be reduced significantly using coarse-grained (CG) methods in which groups of atoms are replaced by beads, allowing longer simulations at the cost of fine details (60).…”
Section: Molecular Dynamics Simulations: Producing Testable Hypothesementioning
confidence: 99%
“…[39][40][41] Although the performance of a free energy scheme is strongly dependent on the required computing resources, US simulations with adequate computing resources often provide highly accurate and precise results. [42][43][44] The approach is especially appropriate to specify the affinity of a ligand binding to a protein/enzyme having a solventexposed binding site, which allows its inhibitor to bind/unbind without significant protein/enzyme conformational transformation. However, calculated values often overestimate experimental ones by about 34%.…”
Section: Introductionmentioning
confidence: 99%