title: Effect of protein backbone folding on the stability of protein-ligand complexes.
abstract: The role played by the degree of folding of protein backbones in explaining the binding energetics of protein-ligand interactions has been studied. We analyzed the protein/peptide interactions in the RNase-S system in which amino acids at two positions of the peptide S have been mutated. The global degree of folding of the protein S correlates in a significant way with the free energy and enthalpy of the protein-peptide interactions. A much better correlation is found with the local contribution to the degree of folding of one amino acid residue: Thr36. This residue is shown to have a destabilizing interaction with Lys41, which interacts directly with peptide S. Another system, consisting of the interactions of small organic molecules with HIV-1 protease was also studied. In this case, the global change in the degree of folding of the protease backbone does not explain the binding energetics of protein-ligand interactions. However, a significant correlation is observed between the free energy of binding and the contribution of two amino acid residues in the HVI-1 protease: Gly49 and Ile66. In general, it was observed that the changes in the degree of folding are not restricted to the binding site of the protein chain but are distributed along the whole protein backbone. This study provides a basis for further consideration of the degree of folding as a parameter for empirical structural parametrizations of the binding energetics of protein folding and binding.
authors.affiliation: Complex Systems Research Group, X-ray Unit, RIAIDT, Edificio CACTUS, University of Santiago de Compostela, 15782 Santiago de Compostela, Spain. estrada66@yahoo.com
authors.forename: Ernesto
authors.initials: E
authors.lastname: Estrada
authors.forename: Eugenio
authors.initials: E
authors.lastname: Uriarte
authors.forename: Santiago
authors.initials: S
authors.lastname: Vilar
mesh_terms: D000596:Amino Acids / Q000737:chemistry; D016333:HIV Protease / Q000737:chemistry*; D017320:HIV Protease Inhibitors / Q000737:chemistry*; D006801:Humans; D008024:Ligands; D015394:Molecular Structure; D010455:Peptides / Q000737:chemistry* / Q000235:genetics; D011487:Protein Conformation; D017510:Protein Folding; D017293:Protein S / Q000737:chemistry* / Q000235:genetics; D012260:Ribonucleases / Q000737:chemistry
chemical_list: D000596:Amino Acids; D017320:HIV Protease Inhibitors; D008024:Ligands; D010455:Peptides; D017293:Protein S; D012260:Ribonucleases; C022542:ribonuclease S; D016333:HIV Protease