Journal
JOURNAL OF COMPUTATIONAL CHEMISTRY
Volume 41, Issue 20, Pages 1804-1819Publisher
WILEY
DOI: 10.1002/jcc.26221
Keywords
alchemical free energy calculation; binding pose; collective variable; metadynamics; reweighting; standard free energy
Categories
Ask authors/readers for more resources
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.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available