Selectivity of Neutral/Weakly Basic P1 Group Inhibitors of Thrombin and Trypsin by a Molecular Dynamics Study

Abstract

Molecular dynamics (MD) simulations followed by molecular mechanics generalized Born surface area (MM-GBSA) analyses have been carried out to study the selectivity of two neutral and weakly basic P1 group inhibitors (177 and CDA) to thrombin and trypsin. Detailed binding free energies between these inhibitors and individual protein residues are calculated by using a per-residue basis decomposition method. The analysis of the detailed interaction energies provides insight on the protein-inhibitor-binding mechanism and helps to elucidate the basis for achieving selectivity through interpretation of the structural and energetic results from the simulations. The study shows that the dominant factor of selectivity for both inhibitors is van der Waals energy, which suggests better shape complementarity and packing with thrombin. Nonpolar solvation free energy and total entropy contribution are also in favor of selectivity, but the contributions are much smaller. Binding mode and structural analysis show that 177 binds to thrombin and trypsin in a similar binding mode. In contrast, the CDA binds to thrombin and trypsin in very different modes.

Flexibility of Short-Strand RNA in Aqueous Solution as Revealed by Molecular Dynamics Simulation: Are A-RNA and A´-RNA Distinct Conformational Structures?

“…After the system was heated at constant volume with weak restraints on RNA, the main MD simulation was performed for 30 ns with a time step of 2 fs under constant pressure (average pressure 1atm) and constant temperature (T=300K) conditions (i.e., an NPT ensemble) without positional restraints. The random number seed was changed at each restart 50,51 and periodic boundary conditions were employed in three dimensions. Isotropic position scaling was used to maintain the pressure and a relaxation time of 2 ps was used.…”

Molecular dynamics simulation reveals preorganization of the chloroplast FtsY towards complex formation induced by GTP binding

“…where SASA was calculated by ICOSA method and c was set to 0.0072 kcal mol À1 Å À2 (Gohlke et al, 2003;Wu et al, 2008). We also demonstrated the decomposition of DG i-binding on a per-residue basis into terms of van der Waals interaction, nonpolar solvation energy, and the sum of coulombic interaction and polar solvation energy.…”

“…Therefore it was not necessary to evaluate the total binding free energy between cpFtsY and GTP molecule by including the time-consuming term of entropy calculation (Jing and Han, 2010;Wu et al, 2008). A total of 225 snapshots of the last 11 ns during the simulation of GTP-cpFtsY were used to calculate the decomposition of binding energies with MM-GBSA module in AMBER10 (Case et al, 2008).…”

Some insights into mechanism for binding and drug resistance of wild type and I50V V82A and I84V mutations in HIV-1 protease with GRL-98065 inhibitor from molecular dynamic simulations

“…7. The decomposed approach is not only extremely useful to elucidate the drug-resistant mechanism at the atomic level, but also helpful to locate residues which contribute to the protease-inhibitor interaction [20]. Comparisons between the inhibitor-residue interaction spectrum of WT and the three mutations I50V, V82A and I84V, are performed.…”