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

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 R2 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.

Automated summary

This study implemented an expanded ensemble workflow and distributed computing to predict binding free energies between small molecules and pillar[6]arene. The results suggest that the expanded ensemble method can efficiently predict and rank absolute binding free energies.