The dawn of alchemical free-energy methods in biomolecular simulations (2510.04917v1)

Abstract: From the onset of fundamental statistical mechanical constructs formulated in the late 19th century, alchemical free-energy methods slowly emerged and transitioned to become operational tools of biomolecular simulation applicable to a wide range of problems including protein-ligand binding for drug discovery research. This article reconstructs how statistical mechanical approaches such as thermodynamic integration and free-energy perturbation were reconfigured in the early 1980's to address the complexities of increasingly heterogeneous biomolecular systems. Drawing on oral history interviews and primary literature, the study examines the technical, institutional, theoretical, and infrastructural conditions under which these methods were implemented, and became progressively operational. These conditions encompassed the consolidation of lab-specific software infrastructures, the formulation of practical simulation protocols, as well as essential statistical mechanical clarifications. From this perspective, the progress of free-energy methods proceeded less from a unified convergence than from an iterative troubleshooting process of alignment involving practical and theoretical considerations. The aim of the present article is to offer a historically grounded account of how free-energy techniques acquired practical and functional reliability.