Separated topologies - A method for relative binding free energy calculations using orientational restraints

Gabriel Rocklin*, David L. Mobley, Ken A. Dill

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

9 Scopus citations

Abstract

Orientational restraints can improve the efficiency of alchemical free energy calculations, but they are not typically applied in relative binding calculations, which compute the affinity difference been two ligands. Here, we describe a new "separated topologies" method, which computes relative binding free energies using orientational restraints and which has several advantages over existing methods. While standard approaches maintain the initial and final ligand in a shared orientation, the separated topologies approach allows the initial and final ligands to have distinct orientations. This avoids a slowly converging reorientation step in the calculation. The separated topologies approach can also be applied to determine the relative free energies of multiple orientations of the same ligand. We illustrate the approach by calculating the relative binding free energies of two compounds to an engineered site in Cytochrome C Peroxidase.

Original languageEnglish (US)
Article number085104
JournalJournal of Chemical Physics
Volume138
Issue number8
DOIs
StatePublished - Feb 28 2013

ASJC Scopus subject areas

  • Physics and Astronomy(all)
  • Physical and Theoretical Chemistry

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