title: Free energy predictions of ligand binding to an α-helix using steered molecular dynamics and umbrella sampling simulations.
abstract: Free energy prediction of ligand binding to macromolecules using explicit solvent molecular dynamics (MD) simulations is computationally very expensive. Recently, we reported a linear correlation between the binding free energy obtained via umbrella sampling (US) versus the rupture force from steered molecular dynamics (SMD) simulations for epigallocatechin-3-gallate (EGCG) binding to α-helical-rich keratin. This linear correlation suggests a potential route for fast free energy predictions using SMD alone. In this work, the generality of the linear correlation is further tested for several ligands interacting with the α-helical motif of keratin. These molecules have significantly varying properties, i.e., octanol/water partition coefficient (log P), and/or overall charges (oleic acid, catechin, Fe(2+), citric acid, hydrogen citrate, dihydrogen citrate, and citrate). Using the constant loading rate of our previous study of the keratin-EGCG system, we observe that the linear correlation for keratin-EGCG can be extended to other uncharged molecules where interactions are governed by hydrogen bonds and/or a combination of hydrogen bonds and hydrophobic forces. For molecules where interactions with the keratin helix are governed primarily by electrostatics between charged molecules, a second, alternative linear correlation model is derived. While further investigations are needed to expand the molecular space and build a fully predictive model, the current approach represents a promising methodology for fast free energy predictions based on short SMD simulations (requiring picoseconds to nanoseconds of sampling) for defined biomolecular systems.
authors.affiliation: National University of Singapore , Department of Biological Sciences, 14 Science Drive 4, Singapore 117543.
authors.forename: Jan K
authors.initials: JK
authors.lastname: Marzinek
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Bond
authors.forename: Guoping
authors.initials: G
authors.lastname: Lian
authors.forename: Yanyan
authors.initials: Y
authors.lastname: Zhao
authors.forename: Lujia
authors.initials: L
authors.lastname: Han
authors.forename: Massimo G
authors.initials: MG
authors.lastname: Noro
authors.forename: Efstratios N
authors.initials: EN
authors.lastname: Pistikopoulos
authors.forename: Athanasios
authors.initials: A
authors.lastname: Mantalaris
mesh_terms: D002392:Catechin / Q000031:analogs & derivatives* / Q000378:metabolism; D007633:Keratins / Q000737:chemistry* / Q000378:metabolism*; D008024:Ligands; D056004:Molecular Dynamics Simulation; D011485:Protein Binding; D055550:Protein Stability; D017433:Protein Structure, Secondary; D013816:Thermodynamics
chemical_list: D008024:Ligands; D007633:Keratins; D002392:Catechin; C045651:epigallocatechin gallate