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Alchemical free energy calculations via metadynamics: Application to the theophylline‐RNA aptamer complex
Author(s) -
Tanida Yoshiaki,
Matsuura Azuma
Publication year - 2020
Publication title -
journal of computational chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.907
H-Index - 188
eISSN - 1096-987X
pISSN - 0192-8651
DOI - 10.1002/jcc.26221
Subject(s) - metadynamics , intramolecular force , binding energy , binding affinities , chemistry , affinities , aptamer , molecular dynamics , inosine , computational chemistry , riboswitch , molecule , chemical physics , crystallography , rna , stereochemistry , physics , quantum mechanics , biology , biochemistry , receptor , organic chemistry , non coding rna , gene , genetics , enzyme
We propose a computational workflow for robust and accurate prediction of both binding poses and their affinities at early stage in designing drug candidates. Small, rigid ligands with few intramolecular degrees of freedom, for example, fragment‐like molecules, have multiple binding poses, even at a single binding site, and their affinities are often close to each other. We explore various structures of ligand binding to a target through metadynamics using a small number of collective variables, followed by reweighting to obtain the atomic coordinates. After identifying each binding pose by cluster analysis, we perform alchemical free energy calculations on each structure to obtain the overall value. We applied this protocol in computing free energy of binding for the theophylline‐RNA aptamer complex. Of the six (meta)stable structures found, the most favorable binding structure is consistent with the structure obtained by NMR. The overall free energy of binding reproduces the experimental values very well.