title: Ligand entry into the calyx of β-lactoglobulin.
abstract: Although the thermodynamic principles that control the binding of drug molecules to their protein targets are well understood, the detailed process of how a ligand reaches a protein binding site has been an intriguing question over decades. The short time interval between the encounter between a ligand and its receptor to the formation of the stable complex has prevented experimental observations. Bovine β-lactoglobulin (βlg) is a lipocalin member that carries fatty acids (FAs) and other lipids in the cellular environment. Βlg accommodates a FA molecule in its highly hydrophobic cavity and exhibits the capability of recognizing a wide variety of hydrophobic ligands. To elucidate the ligand entry process on βlg, we report molecular dynamics simulations of the encounter between palmitate (PA) or laurate (LA) and βlg. Our results show that residues localized in loops at the cavity entrance play an important role in the ligand penetration process. Analysis of the short-term interaction energies show that the forces operating on the systems lead to average conformations very close to the crystallographic holo-forms. Whereas the binding free energy analysis using the molecular mechanics Generalized Born surface area method shows that these conformations were thermodynamically favorable.
authors.affiliation: Laboratorio de Modelado Molecular y Bioinformática de la Escuela Superior de Medicina, Instituto Politécnico Nacional, México. Plan de San Luis Y Diaz Mirón S/N, Col. Casco de Santo Tomas, 11340 México, D. F., México.
authors.forename: Martiniano
authors.initials: M
authors.lastname: Bello
authors.forename: Enrique
authors.initials: E
authors.lastname: García-Hernández
mesh_terms: D000465:Algorithms; D000818:Animals; D001665:Binding Sites; D002417:Cattle; D057927:Hydrophobic and Hydrophilic Interactions; D007700:Kinetics; D007782:Lactoglobulins / Q000737:chemistry* / Q000378:metabolism; D007850:Lauric Acids / Q000737:chemistry / Q000378:metabolism; D008024:Ligands; D008968:Molecular Conformation; D056004:Molecular Dynamics Simulation; D019308:Palmitic Acid / Q000737:chemistry / Q000378:metabolism; D011485:Protein Binding; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D013816:Thermodynamics
chemical_list: D007782:Lactoglobulins; D007850:Lauric Acids; D008024:Ligands; C030358:lauric acid; D019308:Palmitic Acid
keywords: fatty acid; free energy calculation; lactoglobulin; lauric acid; molecular dynamics; palmitic acid