Hamiltonian Mapping Revisited: Calibrating Minimalist Models to Capture Molecular Recognition by Intrinsically...

Molecular recognition by intrinsically disordered proteins (IDPs) plays a central role in many critical cellular processes. Toward achieving detailed mechanistic understanding of IDP-target interactions, here we employ the "Hamiltonian mapping" methodology, which is rooted in the weighted histogram analysis method (WHAM), for the fast and efficient calibration of structure-based models in studies of IDPs. By performing reference simulations on a given Hamiltonian, we illustrate for two model IDPs how this method can extrapolate thermodynamic behavior under a range of modified Hamiltonians, in this case representing changes in the binding affinity (K_d) of the system. Given sufficient conformational sampling in a single trajectory, Hamiltonian mapping accurately reproduces K_d values from direct simulation. This method may be generally applied to systems beyond IDPs in force field optimization and in describing changes in thermodynamic behavior as a function of external conditions for connection with experiment.