Alchemical free energy calculations via metadynamics: Application to the theophylline-RNA aptamer complex.
alchemical free energy calculation
binding pose
collective variable
metadynamics
reweighting
standard free energy
Journal
Journal of computational chemistry
ISSN: 1096-987X
Titre abrégé: J Comput Chem
Pays: United States
ID NLM: 9878362
Informations de publication
Date de publication:
30 07 2020
30 07 2020
Historique:
received:
01
11
2019
revised:
03
04
2020
accepted:
26
04
2020
pubmed:
26
5
2020
medline:
16
6
2021
entrez:
26
5
2020
Statut:
ppublish
Résumé
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.
Substances chimiques
Aptamers, Nucleotide
0
Ligands
0
Theophylline
C137DTR5RG
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
1804-1819Informations de copyright
© 2020 Wiley Periodicals, Inc.
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