title: Hamiltonian Mapping Revisited: Calibrating Minimalist Models to Capture Molecular Recognition by Intrinsically Disordered Proteins.
abstract: 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 (Kd) of the system. Given sufficient conformational sampling in a single trajectory, Hamiltonian mapping accurately reproducesKdvalues 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.
authors.affiliation: Department of Chemistry and Biophysics Program, The University of Michigan , Ann Arbor, Michigan 48109, United States.
authors.forename: Sean M
authors.initials: SM
authors.lastname: Law
authors.affiliation: Department of Chemistry and Biophysics Program, The University of Michigan , Ann Arbor, Michigan 48109, United States.
authors.forename: Logan S
authors.initials: LS
authors.lastname: Ahlstrom
authors.affiliation: Department of Chemistry and Biophysics Program, The University of Michigan , Ann Arbor, Michigan 48109, United States.
authors.forename: Afra
authors.initials: A
authors.lastname: Panahi
authors.affiliation: Department of Chemistry and Biophysics Program, The University of Michigan , Ann Arbor, Michigan 48109, United States.
authors.forename: Charles L
authors.initials: CL
authors.lastname: Brooks