title: Web application for studying the free energy of binding and protonation states of protein-ligand complexes based on HINT.
abstract: A public web server performing computational titration at the active site in a protein-ligand complex has been implemented. This calculation is based on the Hydropathic interaction noncovalent force field. From 3D coordinate data for the protein, ligand and bridging waters (if available), the server predicts the best combination of protonation states for each ionizable residue and/or ligand functional group as well as the Gibbs free energy of binding for the ionization-optimized protein-ligand complex. The 3D structure for the modified molecules is available as output. In addition, a graph depicting how this energy changes with acidity, i.e., as a function of added protons, can be obtained. This data may prove to be of use in preparing models for virtual screening and molecular docking. A few illustrative examples are presented. In beta secretase (2va7) computational titration flipped the amide groups of Gln12 and Asn37 and protonated a ligand amine yielding an improvement of 6.37 kcal mol(-1) in the protein-ligand binding score. Protonation of Glu139 in mutant HIV-1 reverse transcriptase (2opq) allows a water bridge between the protein and inhibitor that increases the protein-ligand interaction score by 0.16 kcal mol(-1). In human sialidase NEU2 complexed with an isobutyl ether mimetic inhibitor (2f11) computational titration suggested that protonating Glu218, deprotonating Arg237, flipping the amide bond on Tyr334, and optimizing the positions of several other polar protons would increase the protein-ligand interaction score by 0.71 kcal mol(-1).
authors: Department of Medicinal Chemistry & Institute for Structural Biology and Drug Discovery, Virginia Commonwealth University, Richmond, VA 23298-0540, USA.
authors: Alexander S
authors: AS
authors: Bayden
authors: Micaela
authors: M
authors: Fornabaio
authors: J Neel
authors: JN
authors: Scarsdale
authors: Glen E
authors: GE
authors: Kellogg
mesh_terms: D000465:Algorithms; D000596:Amino Acids / Q000737:chemistry; D053829:Amyloid Precursor Protein Secretases / Q000737:chemistry / Q000378:metabolism; D019295:Computational Biology / Q000379:methods*; D003196:Computer Graphics; D018360:Crystallography, X-Ray; D054303:HIV Reverse Transcriptase / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D006863:Hydrogen-Ion Concentration; D057927:Hydrophobic and Hydrophilic Interactions; D020407:Internet; D008024:Ligands; D008956:Models, Chemical; D015394:Molecular Structure; D009439:Neuraminidase / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D011485:Protein Binding; D011522:Protons; D012997:Solvents / Q000737:chemistry; D013816:Thermodynamics; D017186:Titrimetry
chemical_list: D000596:Amino Acids; D008024:Ligands; D011522:Protons; D012997:Solvents; C514824:reverse transcriptase, Human immunodeficiency virus 1; D054303:HIV Reverse Transcriptase; C403285:NEU2 protein, human; D009439:Neuraminidase; D053829:Amyloid Precursor Protein Secretases