title: Computational analysis of the binding affinities of the natural-product cyclopentapeptides argifin and argadin to chitinase B from Serratia marcescens.
abstract: Molecular dynamics (MD) simulations and the molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) method were applied to study the interaction of the natural-product cyclopentapeptide chitinase inhibitors argifin and argadin with chitinase B (ChiB) from Serratia marcescens. Argadin inhibited ChiB with an inhibition constant (K(i)) value of 20 nM, which was three orders of magnitude greater than that of argifin (K(i)=33,000 nM). The MM-PBSA free-energy analysis provided absolute binding free energies of -6.98 and -11.16 kcal/mol for the argifin and argadin complexes, respectively. These estimates were in good agreement with the free energies derived from the experimental K(i) values (-6.36 and -10.92 kcal/mol for the argifin and argadin complexes, respectively). The energetic analysis revealed that the van der Waals and nonpolar solvation energies drove the binding of both argifin and argadin. We found that the binding of argadin gained approximately 12 kcal/mol more van der Waals energy than that of argifin, which was mainly responsible for the difference in binding free energy between argifin and argadin. In particular, W220 and W403 of ChiB were found to contribute to the more favorable van der Waals interaction with argadin. We also designed argifin derivatives with better binding affinity, in which a constituent amino-acid residue of argifin was mutated to one with a bulky side chain. The derivative in which D-Ala of argifin was replaced with D-Trp appeared to possess a binding affinity that was equally potent to that of argadin.
authors.affiliation: School of Pharmaceutical Sciences, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, Japan. godah@pharm.kitasato-u.ac.jp
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Gouda
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Yanai
authors.forename: Akihiro
authors.initials: A
authors.lastname: Sugawara
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Sunazuka
authors.forename: Satoshi
authors.initials: S
authors.lastname: Omura
authors.forename: Shuichi
authors.initials: S
authors.lastname: Hirono
mesh_terms: D001688:Biological Products / Q000737:chemistry* / Q000378:metabolism; D002688:Chitinases / Q000378:metabolism*; D003198:Computer Simulation; D018360:Crystallography, X-Ray; D006860:Hydrogen Bonding; D008958:Models, Molecular; D015394:Molecular Structure; D010456:Peptides, Cyclic / Q000737:chemistry* / Q000378:metabolism*; D011485:Protein Binding; D012706:Serratia marcescens / Q000737:chemistry*
chemical_list: D001688:Biological Products; D010456:Peptides, Cyclic; C419444:argadin; C413566:argifin; D002688:Chitinases