Free energy predictions of ligand binding to an -helix using steered molecular dynamics and umbrella sampling simulations. Academic Article uri icon


  • 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 -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 -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.

published proceedings

  • J Chem Inf Model

altmetric score

  • 1

author list (cited authors)

  • Marzinek, J. K., Bond, P. J., Lian, G., Zhao, Y., Han, L., Noro, M. G., Pistikopoulos, E. N., & Mantalaris, A.

citation count

  • 13

complete list of authors

  • Marzinek, Jan K||Bond, Peter J||Lian, Guoping||Zhao, Yanyan||Han, Lujia||Noro, Massimo G||Pistikopoulos, Efstratios N||Mantalaris, Athanasios

publication date

  • July 2014