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.

Computational mechanistic study of human liver glycerol 3‐phosphate dehydrogenase using ONIOM method

“…[13] Experimental studies could be complemented with the calculations involving ONIOM method treating active site quantum mechanically and the surrounding environment with molecular mechanics. [14][15][16][17][18][19] The enzymatic transformations could be investigated with DFT calculations, and the surrounding residues could be treated with molecular mechanics methods in order to include steric constraints induced by the protein environment and the contribution of the noncovalent interactions around the active sites.…”

Insights into the stereoselectivity of human SETD7 methyltransferase

“…The method of QM/MM-GBSA get great success to investigate the interaction of inhibitors binding to targets as reported in everywhere. [25][26][27] Here, the hybrid method of semi-empirical Hamiltonian PM6 and MM-GBSA was chosen to calculate binding free energies between hSETD7 and PFI-2 enantiomers to detect the hidden information behind the stereoselectivity of hSETD7. 200 frames collected from the nal 40 ps of QM/MM MD trajectory with an interval of 200 fs were used for calculating the binding energies.…”

“…In order to more accurately investigate the hydrogen bond for insight into the stereoselectivity of hSETD7 methyltransferase to the (R/S)-PFI-2, we used the hybrid quantum mechanics/molecular mechanics (QM/MM) MD simulations that had been successfully applied in many researches. [25][26][27] In this study, the QM regions were displayed in Fig. 3, where the average surface of electrostatic potential (EPS) was plotted.…”

RM1 Semiempirical Model: Chemistry, Pharmaceutical Research, Molecular Biology and Materials Science

“…Chen et al 264 compared the performance of several semiempirical methods, including RM1, as well as DFT, in the investigation of hydrogen bonds and polar interactions of two inhibitors of the enzyme trypsin. Results showed that PM6 was the best semiempirical method to describe the interactions between the ligands and trypsin.…”

“…Results showed that PM6 was the best semiempirical method to describe the interactions between the ligands and trypsin. 264 In addition, the authors predicted Δ bind G (Gibbs energy of binding) of the two ligands on trypsin by using QM/MM GBSA (generalized Born and surface-area solvation) methodology. The results revealed that all computational methods gave similar results for such property.…”