Terminal-Flip Monte Carlo: Accelerating the Convergence of Molecular Dynamics and Alchemical Free Energy Calculations

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 (TFMC) move specifically designed to accelerate conformational sampling in alchemical simulations. We integrated TFMC into alchemical RBFE calculations of protein–ligand complexes and benchmarked it on JNK1, cMet, SHP2, Thrombin, and Factor Xa systems. TFMC yields a 2–5× faster convergence of key dihedral distributions and improves ΔΔ G estimates by up to 1 kcal/mol compared with conventional molecular dynamics (MD) simulation-based FEP. Our method removes sampling biases in scaffold-hopping transformations and is straightforward to implement in existing FEP workflows.