Free-Energy Landscape Analysis of Protein-Ligand Binding: The Case of Human Glutathione Transferase A1

Glutathione transferases (GSTs) are a superfamily of enzymes which have in common the ability to catalyze nucleophilic addition thiol group reduced glutathione (GSH) onto electrophilic and hydrophobic substrates. This conjugation reaction, occurs spontaneously but is dramatically accelerated by enzyme, protects cells against damages caused harmful molecules. With some exceptions, GSTs catalytically active as homodimers, with monomers generally constituted 200 250 residues organized into two subdomains. The first N-terminal subdomain, contains an site named G site, where GSH hosted catalytic conformation highly conserved among GSTs. second hydrophobic, binds substrate counterpart (H site), can vary from one GST another, resulting structures able recognize different In present work, we performed all-atom molecular dynamics simulations explicit solvent human GSTA1 its APO form, bound ligand GS-conjugated ligand. From MD, probes were analyzed (i) decipher local conformational changes induced presence (ii) map communication pathways involved ligand-binding process. These are, first, coarse-grained angles (θ,γ), representing protein main chain and, second, dihedral χ amino-acid side chains. time series, effective free-energy landscapes along sequence compared between three forms GSTA1. methodology allowed us extract network 33 key residues, them being located experimentally well-known binding sites H others far 30Å original sites. Finally, collective motions associated established, showing strong dynamical coupling Gly14-Arg15 Gln54-Val55, both same (intrasite) also each monomer (intersites).