title: Binding Energy Distribution Analysis Method: Hamiltonian Replica Exchange with Torsional Flattening for Binding Mode Prediction and Binding Free Energy Estimation.
abstract: Molecular dynamics modeling of complex biological systems is limited by finite simulation time. The simulations are often trapped close to local energy minima separated by high energy barriers. Here, we introduce Hamiltonian replica exchange (H-REMD) with torsional flattening in the Binding Energy Distribution Analysis Method (BEDAM), to reduce energy barriers along torsional degrees of freedom and accelerate sampling of intramolecular degrees of freedom relevant to protein-ligand binding. The method is tested on a standard benchmark (T4 Lysozyme/L99A/p-xylene complex) and on a library of HIV-1 integrase complexes derived from the SAMPL4 blind challenge. We applied the torsional flattening strategy to 26 of the 53 known binders to the HIV Integrase LEDGF site found to have a binding energy landscape funneled toward the crystal structure. We show that our approach samples the conformational space more efficiently than the original method without flattening when starting from a poorly docked pose with incorrect ligand dihedral angle conformations. In these unfavorable cases convergence to a binding pose within 2-3 Å from the crystallographic pose is obtained within a few nanoseconds of the Hamiltonian replica exchange simulation. We found that torsional flattening is insufficient in cases where trapping is due to factors other than torsional energy, such as the formation of incorrect intramolecular hydrogen bonds and stacking. Work is in progress to generalize the approach to handle these cases and thereby make it more widely applicable.
authors.forename: Ahmet
authors.initials: A
authors.lastname: Mentes
authors.forename: Nan-Jie
authors.initials: NJ
authors.lastname: Deng
authors.forename: R S K
authors.initials: RS
authors.lastname: Vijayan
authors.forename: Junchao
authors.initials: J
authors.lastname: Xia
authors.affiliation: Department of Chemistry, Brooklyn College, The City University of New York , Brooklyn, New York 11210, United States.
authors.forename: Emilio
authors.initials: E
authors.lastname: Gallicchio
authors.forename: Ronald M
authors.initials: RM
authors.lastname: Levy
mesh_terms: D018360:Crystallography, X-Ray; D005544:Forecasting; D019427:HIV Integrase / Q000737:chemistry* / Q000378:metabolism; D056004:Molecular Dynamics Simulation; D011485:Protein Binding / Q000502:physiology; D017433:Protein Structure, Secondary; D054159:Torsion, Mechanical; D014992:Xylenes / Q000737:chemistry* / Q000378:metabolism
chemical_list: D014992:Xylenes; C031286:4-xylene; D019427:HIV Integrase; C514801:p31 integrase protein, Human immunodeficiency virus 1