Expanded ensemble predictions of absolute binding free energies in the SAMPL9 host-guest challenge

• Published in: Physical chemistry chemical physics : PCCP 2023-12, Vol.25 (47), p.32393-3246
• Main Authors: Hurley, Matthew F. D, Raddi, Robert M, Pattis, Jason G, Voelz, Vincent A
• Format: Article
• Language: English
• Subjects: Binding; Computer networks; Distributed processing; Free energy; Molecular dynamics; Protonation; Software; Workflow
• ISSN: 1463-9076; 1463-9084; 1463-9084
• DOI: 10.1039/d3cp02197a

As part of the SAMPL9 community-wide blind host-guest challenge, we implemented an expanded ensemble workflow to predict absolute binding free energies for 13 small molecules against pillar[6]arene. Notable features of our protocol include consideration of a variety of protonation and enantiomeric states for both host and guests, optimization of alchemical intermediates, and analysis of free energy estimates and their uncertainty using large numbers of simulation replicates performed using distributed computing. Our predictions of absolute binding free energies resulted in a mean absolute error of 2.29 kcal mol −1 and an R 2 of 0.54. Overall, results show that expanded ensemble calculations using all-atom molecular dynamics simulations are a valuable and efficient computational tool in predicting absolute binding free energies. An expanded ensemble (EE) method was deployed in distributed molecular simulations to make blind predictions of host-guest binding affinities in SAMPL9. Results suggest EE can efficiently predict and rank absolute binding free energies.