Molecular and thermodynamic basis for EGCG‐Keratin interaction‐part I: Molecular dynamics simulations

Abstract

Nonspecific binding of small molecules to proteins influences transdermal permeation and intestinal absorption, yet understanding of the molecular and thermodynamic basis is still limited. In this study, we report all-atom, fully solvated molecular dynamics simulations of the thermodynamic characteristics of epigallocatechin-3-gallate (EGCG) binding keratin. Experimental validation is reported in Part II. Herein, 18 μs of simulation sampling was calculated. We show that the binding process is a combination of hydrophobic interaction, hydrogen bonding and aromatic interaction. The umbrella sampling technique was used to calculate the binding free energy of EGCG with keratin segments. By extracting EGCG from the keratin-EGCG complex using steered molecular dynamics, the rupture force was observed to be linearly related to the binding free energy. Multilayer binding of EGCG clusters to keratin has been shown. The binding free energy of -6.2 kcal mol obtained from the simulations was in excellent agreement with the experimental Part II. © 2013 American Institute of Chemical Engineers

Free Energy Predictions of Ligand Binding to an α-Helix Using Steered Molecular Dynamics and Umbrella Sampling Simulations

“…25 Recently, we reported a linear dependency between the maximum pulling force obtained from SMD simulations and the free energies obtained via US, for epigallocatechin-3-gallate (EGCG) interacting with keratin (helical segments). 16 Previously, Mai et al 26,27 proposed a similar linear correlation for ligands binding to swine influenza A/H1N1 virus between the average rupture force (maximum pulling force) at constant loading rate (spring constant times pulling velocity), over 4 SMD trajectories, and the experimentally confirmed and MM/ PBSA-based binding free energies. These findings, and the fact that the α-helix is the most prevalent protein secondary structure 28 accounting for 30% of the average globular protein, 29 motivated us to test and extend the keratin-EGCG linear dependency for other ligands.…”

“…Not all molecules studied herein with ranging physicochemical properties followed the linear correlation that we observed in a previous study. 16 The linear correlation observed for keratin−EGCG could be only extended to molecules with a total charge of zero where the interaction is governed by hydrogen bonds (citric acid) and/or a combination of hydrogen bonds and hydrophobic interactions (catechin). For molecules where interactions are primarily governed by electrostatics between charged molecules (dihydrogen citrate, hydrogen citrate, citrate, and the previously studied ferrous ion 19 ), a second (different) linear correlation is observed.…”

Atomistic modeling of a KRT35/KRT85 keratin dimer: folding in aqueous solution and unfolding under tensile load

“…In lack of information from crystal structure refinement (keratin dimers do not form crystals), so far only approximant models were subjected to molecular modelling. [1][2][3][4] Therein, the well-established alpha-helical parts of keratin dimers were considered (these fragments could be made accessible to crystal structure refinement ten years ago 5 ), leaving out the less-ordered head, tail and the linker fragments (see also Fig. 1).…”

A Study on Fe2+ – α-Helical-Rich Keratin Complex Formation Using Isothermal Titration Calorimetry and Molecular Dynamics Simulation

“…Reported studies of such ferrous ion binding include Escherichia coli ferritin, recombinant human H‐Chain ferritin, and yeast frataxin . Because of the advantage of yielding atomically detailed data regarding the assessment of binding sites and associated conformational changes within proteins, molecular dynamics (MD) simulations of ligand–protein interaction have recently provided complementary information . A study using quantum mechanical–molecular mechanical approaches reported the possibility of three different interactions between ferrous ion and an α‐helical peptide, and η 2 (O,O) coordination modes were reported as the most stable type.…”

“…15 Because of the advantage of yielding atomically detailed data regarding the assessment of binding sites and associated conformational changes within proteins, molecular dynamics (MD) simulations of ligand-protein interaction have recently provided complementary information. [16][17][18][19] A study 20 using quantum mechanical-molecular mechanical approaches reported the possibility of three different interactions between ferrous ion and an "-helical peptide, and 0 2 (O,O) coordination modes were reported as the most stable type. However, this simulation was based upon an ideal protein environment and neglected solvent effects.…”