Multisecond ligand dissociation dynamics from atomistic simulations

Abstract: Coarse-graining of fully atomistic molecular dynamics simulations is a long-standing goal inorder to allow the description of processes occurring on biologically relevant timescales. Forexample, the prediction of pathways, rates and rate-limiting steps in protein-ligand unbindingis crucial for modern drug discovery. To achieve the enhanced sampling, we performdissipation-corrected targeted molecular dynamics simulations, which yield free energy andfriction profiles of molecular processes under consideration. Subsequently, we use thesefields to perform temperature-boosted Langevin simulations which account for the desiredkinetics occurring on multisecond timescales and beyond. Adopting the dissociation of sol-vated sodium chloride, trypsin-benzamidine and Hsp90-inhibitor protein-ligand complexes astest problems, we reproduce rates from molecular dynamics simulation and experimentswithin a factor of 2–20, and dissociation constants within a factor of 1–4. Analysis of frictionprofiles reveals that binding and unbinding dynamics are mediated by changes of the sur-rounding hydration shells in all investigated systems

Object Details

• Location: Deutsche Nationalbibliothek Frankfurt am Main
• Extent: Online-Ressource
• Language: Englisch
• Notes: Nature communications. - 11 (2020) , 2918, ISSN: 2041-1723

Contributors, Places and Time

• Event: Veröffentlichung
• (where): Freiburg
• (who): Universität
• (when): 2020
• Creator: Wolf, Steffen ; Lickert, Benjamin ; Bray, Simon A. ; Stock, Gerhard

Further information

• DOI: 10.1038/s41467-020-16655-1
• URN: urn:nbn:de:bsz:25-freidok-1663405
• Rights: Der Zugriff auf das Objekt ist unbeschränkt möglich.
• Last update: 25.03.2025, 1:52 PM CET