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Free energy predictions of ligand binding to an α-helix using steered molecular dynamics and umbrella sampling simulations.

Marzinek, JK, Bond, PJ, Lian, G, Zhao, Y, Han, L, Noro, MG, Pistikopoulos, EN and Mantalaris, A (2014) Free energy predictions of ligand binding to an α-helix using steered molecular dynamics and umbrella sampling simulations. J Chem Inf Model, 54 (7). pp. 2093-2104.

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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.

Item Type: Article
Divisions : Surrey research (other units)
Authors :
Marzinek, JK
Bond, PJ
Zhao, Y
Han, L
Noro, MG
Pistikopoulos, EN
Mantalaris, A
Date : 28 July 2014
DOI : 10.1021/ci500164q
Uncontrolled Keywords : Catechin, Keratins, Ligands, Molecular Dynamics Simulation, Protein Binding, Protein Stability, Protein Structure, Secondary, Thermodynamics
Related URLs :
Depositing User : Symplectic Elements
Date Deposited : 17 May 2017 13:18
Last Modified : 24 Jan 2020 23:46

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