title: Specific interactions and binding free energies between thermolysin and dipeptides: molecular simulations combined with ab initio molecular orbital and classical vibrational analysis.
abstract: Thermolysin (TLN) is a metalloprotease widely used as a nonspecific protease for sequencing peptide and synthesizing many useful chemical compounds by the chemical industry. It was experimentally shown that the activity and functions of TLN are inhibited by the binding of many types of amino acid dipeptides. However, the binding mechanisms between TLN and dipeptides have not been clarified at the atomic and electronic levels. In this study, we investigated the binding mechanisms between TLN and four dipeptides. Specific interactions and binding free energies (BFEs) between TLN and the dipeptides were calculated using molecular simulations based on classical molecular dynamics and ab initio fragment molecular orbital (FMO) methods. The molecular systems were embedded in solvating water molecules during calculations. The calculated BFEs were qualitatively consistent with the trend of the experimentally observed inhibition of TLN activity by binding of the dipeptides. In addition, the specific interactions between the dipeptides and each amino acid residue of TLN or solvating water molecules were elucidated by the FMO calculations.
authors.affiliation: Department of Computer Science and Engineering, Toyohashi University of Technology, Tempaku-cho, Aichi 441-8580, Japan.
authors.forename: Kenichi
authors.initials: K
authors.lastname: Dedachi
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Hirakawa
authors.forename: Seiya
authors.initials: S
authors.lastname: Fujita
authors.forename: Mahmud Tareq Hassan
authors.initials: MT
authors.lastname: Khan
authors.forename: Ingebrigt
authors.initials: I
authors.lastname: Sylte
authors.forename: Noriyuki
authors.initials: N
authors.lastname: Kurita
mesh_terms: D001665:Binding Sites; D004151:Dipeptides / Q000737:chemistry*; D006860:Hydrogen Bonding; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D011789:Quantum Theory; D013816:Thermodynamics; D013820:Thermolysin / Q000737:chemistry* / Q000378:metabolism; D014732:Vibration
chemical_list: D004151:Dipeptides; D013820:Thermolysin