title: A comparative study of trypsin specificity based on QM/MM molecular dynamics simulation and QM/MM GBSA calculation.
abstract: Hydrogen bonding and polar interactions play a key role in identification of protein-inhibitor binding specificity. Quantum mechanics/molecular mechanics molecular dynamics (QM/MM MD) simulations combined with DFT and semi-empirical Hamiltonian (AM1d, RM1, PM3, and PM6) methods were performed to study the hydrogen bonding and polar interactions of two inhibitors BEN and BEN1 with trypsin. The results show that the accuracy of treating the hydrogen bonding and polar interactions using QM/MM MD simulation of PM6 can reach the one obtained by the DFT QM/MM MD simulation. Quantum mechanics/molecular mechanics generalized Born surface area (QM/MM-GBSA) method was applied to calculate binding affinities of inhibitors to trypsin and the results suggest that the accuracy of binding affinity prediction can be significantly affected by the accurate treatment of the hydrogen bonding and polar interactions. In addition, the calculated results also reveal the binding specificity of trypsin: (1) the amidinium groups of two inhibitors generate favorable salt bridge interaction with Asp189 and form hydrogen bonding interactions with Ser190 and Gly214, (2) the phenyl of inhibitors can produce favorable van der Waals interactions with the residues His58, Cys191, Gln192, Trp211, Gly212, and Cys215. This systematic and comparative study can provide guidance for the choice of QM/MM MD methods and the designs of new potent inhibitors targeting trypsin.
authors.affiliation: a School of Science , Shandong Jiaotong University , Jinan , 250014 , China.
authors.forename: Jianzhong
authors.initials: J
authors.lastname: Chen
authors.affiliation: b Discovery and Design Center , CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences , 555 Zuchongzhi Road, Shanghai , 201203 , China.
authors.forename: Jinan
authors.initials: J
authors.lastname: Wang
authors.affiliation: c College of Physics and Electronics , Shandong Normal University , Jinan , 250014 , China.
authors.forename: Qinggang
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: b Discovery and Design Center , CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences , 555 Zuchongzhi Road, Shanghai , 201203 , China.
authors.forename: Kaixian
authors.initials: K
authors.lastname: Chen
authors.affiliation: b Discovery and Design Center , CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences , 555 Zuchongzhi Road, Shanghai , 201203 , China.
authors.forename: Weiliang
authors.initials: W
authors.lastname: Zhu
mesh_terms: D000465:Algorithms; D001665:Binding Sites; D001667:Binding, Competitive; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000378:metabolism; D006860:Hydrogen Bonding; D056004:Molecular Dynamics Simulation; D015394:Molecular Structure; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011789:Quantum Theory; D013816:Thermodynamics; D014357:Trypsin / Q000737:chemistry* / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D014357:Trypsin
keywords: MM-GBSA method, trypsin specificity; QM/MM molecular dynamics simulations; binding free energies; semi-empirical Hamiltonian