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 a-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 a-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, Fe2+, 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. |
Year | DOI | Venue |
---|---|---|
2014 | 10.1021/ci500164q | JOURNAL OF CHEMICAL INFORMATION AND MODELING |
Field | DocType | Volume |
Octanol,Umbrella sampling,Macromolecule,Ligand (biochemistry),Molecule,Ligand,Computational chemistry,Chemistry,Helix,Molecular dynamics | Journal | 54 |
Issue | ISSN | Citations |
7 | 1549-9596 | 1 |
PageRank | References | Authors |
0.37 | 9 | 8 |
Name | Order | Citations | PageRank |
---|---|---|---|
Jan K. Marzinek | 1 | 1 | 0.71 |
Peter J Bond | 2 | 24 | 4.30 |
Guoping Lian | 3 | 1 | 0.37 |
Yanyan Zhao | 4 | 1 | 0.37 |
Lujia Han | 5 | 1 | 0.37 |
Massimo G. Noro | 6 | 1 | 0.37 |
Efstratios N. Pistikopoulos | 7 | 1203 | 153.85 |
Athanasios Mantalaris | 8 | 47 | 8.23 |