Impact of protein conformations on binding free energy calculations in the beta-secretase 1 system.
RBFE
beta‐secretase
binding free energy
conformational changes
molecular dynamics
sampling problems
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:
09 May 2024
09 May 2024
Historique:
revised:
13
01
2024
received:
12
09
2023
accepted:
24
03
2024
medline:
10
5
2024
pubmed:
10
5
2024
entrez:
10
5
2024
Statut:
aheadofprint
Résumé
In binding free energy calculations, simulations must sample all relevant conformations of the system in order to obtain unbiased results. For instance, different ligands can bind to different metastable states of a protein, and if these protein conformational changes are not sampled in relative binding free energy calculations, the contribution of these states to binding is not accounted for and thus calculated binding free energies are inaccurate. In this work, we investigate the impact of different beta-sectretase 1 (BACE1) protein conformations obtained from x-ray crystallography on the binding of BACE1 inhibitors. We highlight how these conformational changes are not adequately sampled in typical molecular dynamics simulations. Furthermore, we show that insufficient sampling of relevant conformations induces substantial error in relative binding free energy calculations, as judged by a variation in calculated relative binding free energies up to 2 kcal/mol depending on the starting protein conformation. These results emphasize the importance of protein conformational sampling and pose this BACE1 system as a challenge case for further method development in the area of enhanced protein conformational sampling, either in combination with binding calculations or as an endpoint correction.
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : NIGMS NIH HHS
ID : R01GM108889
Pays : United States
Organisme : NIGMS NIH HHS
ID : R35GM148236
Pays : United States
Informations de copyright
© 2024 Wiley Periodicals LLC.
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