Alchemical FEP Calculations of Ligand Conformer Focusing in Explicit Solvent

Slow rotational degrees of freedom in ligands can make alchemical FEP simulations unreliable due to inadequate sampling. We addressed this problem by introducing a FEP-based protocol of ligand conformer focusing in explicit solvent. Our method involves FEP transformations between conformers using eq...

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Published inJournal of chemical theory and computation Vol. 9; no. 2; pp. 1093 - 1102
Main Authors Zeifman, Alexey A, Stroylov, Victor V, Novikov, Fedor N, Stroganov, Oleg V, Kulkov, Val, Chilov, Ghermes G
Format Journal Article
LanguageEnglish
Published United States American Chemical Society 12.02.2013
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Summary:Slow rotational degrees of freedom in ligands can make alchemical FEP simulations unreliable due to inadequate sampling. We addressed this problem by introducing a FEP-based protocol of ligand conformer focusing in explicit solvent. Our method involves FEP transformations between conformers using equilibrium dihedral angle as a reaction coordinate and provides the cost of “focusing” on one specific conformational state that binds to a protein. The calculated conformer focusing term made a considerable difference of 5–10 kJ/mol in computed relative binding free energies of studied Syk inhibitors and significantly improved the resulting accuracy of predictions.
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ISSN:1549-9618
1549-9626
DOI:10.1021/ct300796g