Terminal-flip Monte Carlo improves convergence of binding free energies in protein-ligand complexes, suggesting enhanced predictive power for drug design.
Free energy perturbation (FEP) methods have become indispensable for predicting relative binding free energies (RBFE) in lead optimization, yet they often suffer from slow convergence due to high-energy barriers in ligand conformational sampling. In this work, we introduce and validate a terminal-flip Monte Carlo move specifically designed to accelerate conformational sampling in alchemical simulations. We integrated terminal-flip Monte Carlo into alchemical RBFE calculations of protein–ligand complexes and benchmarked it on MCL1, JNK1, and Factor Xa systems. Terminal-flip Monte Carlo yields a 2-5× faster convergence of key dihedral distributions and improves ∆∆G estimates by up to 1 kcal/mol compared with conventional MD-based FEP. Our method removes sampling biases in scaffold-hopping transformations and is straightforward to implement in existing FEP workflows.
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Wang et al. (2025) studied this question.
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