Molecular Dynamics Simulation And Free Energy Calculation Study Several Biological Systems

Molecular dynamics simulations followed by free energy analysis have been carried out to study the binding mode of FKBP12 protein with a set of inhibitors, MDM2 protein with a set of inhibitors, scFv with two inhibitors and HIV-1 viral protease with IDV and GRL-98065 two inhibitors, and analyze the influences caused by mutations in protease and inhibitor complexes. Molecular dynamics simulations have been carried out to show the effects of residue 174 in two different protonation states (Hsd174 and Hse174) and the gating mechanism of the SF.FKBP12 (FK506-binding proteins-12) plays important roles in the treatment of nerve injuries and neurodegenerative disorders. In the paper, the absolute binding free energy of FKBP12 with three potent inhibitors (GPI-1046, 308 and 107) was calculated by molecular dynamics simulation with MM-GBSA method,GPI-1046 has the weakest binding energy, 308 has weaker binding energy than 107. The analysis of detailed interaction energies provides insight on the protein-ligand binding mechanism. Study show that the three inhibitors bind to FKBP12 in a very similar inhibition mode and the calculated data agree well with the experimental data.In order to elucidate the influences of V82A and L90M mutations on the HIV-1 protease and the IDV complex, molecular dynamics simulations have been successfully carried out for 5.5 nanoseconds. The binding free energies calculated by an MM-PBSA method are in agreement with the experimental ones. The analysis of the detailed interaction energies shows that the changes of entropic contribution in V82A and L90M complex are larger than changes of enthalpic contribution compared with the wild complex. Detailed binding free energies of the IDV and individual protein residues show that the wild, V82A and L90M complexes have a similar binding mode, and the binding free energies mainly come from six groups around A28/A28', I50/I50'and I84/I84'. The mode between wild and IDV was analyzed in detail, the little changes of V82A were also compared with L90M. The changes of V82A mutation are caused by the steric hindrance, and those of L90M are by the stronger interaction between D25 and L90 compared with the wild. The single mutations I50V, V82A and I84V are considered as the key residue mutations of the HIV-1 protease drug resistance. The rank of calculated absolute binding free energies using by MM-PBSA method is in excellent agreement with experimental result for protease and GRL-98065 complexes. Enthalpic and entropic balance is analyzed to explain resistance in I50V and V82A having a higher entropic contribution than in the wild type (WT) complex. The reduced van der Waals energy explains the drug resistance of I84V to GRL-98065. Detailed binding free energies between GRL-98065 and individual protein residues are calculated to provide insights into the inhibitor-protein binding and drug-resistant mechanism. Our results show I50V and V82A have larger structural changes than I84V compared with WT.It is a new and promising strategy for anticancer drug design to block the MDM2-p53 interaction using a non-peptide small-molecule inhibitor. We carry out molecular dynamics simulations to study the binding of a set of 6 non-peptide small molecule inhibitors with the MDM2. The absolute binding free energies calculated using molecular mechanics Poisson-Boltzmann surface area method produce a good correlation with experimentally determined. The study shows that the van der Waals energies are the largest component of the binding free energy for each complex, which indicates that the affinities of these inhibitors for MDM2 are dominated by shape complementarity. The quantum mechanics and the binding free energies calculation also show the B-ligands are more possible conformation of ligands. Detailed binding free energies between inhibitors and individual protein residues are calculated to provide insights into the inhibitor-protein binding model through interpretation of the structural and energetic results from the simulations. The study shows that G1, G2 and G3 group mimic the Phe19, Trp23 and Leu26 residues in p53 and their interactions with MDM2, but the binding model of G4 group differs from the original design strategy to mimic Leu22 residue in p53.Molecular dynamics simulations and free energy calculation have been performed to study how the single-chain variable fragment (scFv) binds Methamphetamine (METH) and Amphetamine (AMP). The structural comparison between scFv:METH complex and scFv:AMP complex are carried out by using RMSD, the distance analysis, and the averaged structure. This indicates that binding AMP to the scFv does not change the binding pocket of the scFv:ligand complex. This is not in agreement with the experimental results. The binding free energy of scFv:AMP is smaller than scFv:METH. This is not in agreement with the experimental. However, the binding free energy of the complex (scFv:AMP-WAT), which the methyl group is replaced by a water molecule, is larger than scFv:METH. This is consistent with the experimental. Decomposition of the ligand-residue pair shows that two residues (Tyr175 and Tyr177) have nearly-zero interactions with AMP in the scFv:AMP-WAT complex, whereas the two residues have significant interaction with METH in the scFv:METH complex. The static interaction for Glu114 is more favorable in scFv:AMP-WAT than in scFv:METH complex. The insights gained from this study may be helpful in designing more potent antibodies in treating METH abuse.Aquaporin Z (AQPZ) is a tetrameric protein that forms water channels in Escherichia coli's cell membrane. The histidine residue (Residue 174) in the selectivity filter (SF) region plays an important role in the transport of water across the membrane. In this work, we perform equilibrium molecular dynamics (MD) simulations to illustrate influences of Residue 174 in two different protonation states (Hsd174 and Hse174) and the gating mechanism of the SF. We calculate the pore radii in the SF region versus the simulation time. We perform steered MD to compute the free energy profile, i.e., the potential of mean force (PMF) of a water molecule through the SF region. We conduct quantum mechanics calculation of the binding energy of one water molecule with the residues in the SF region. The hydrogen bonds formed between the side chain of Hsd174 and side chain of Residue 189 (Arg189) play important roles in the selectivity mechanism of AQPZ. The radii of the pores, the hydrogen bond analysis, and the free energies show that AQPZ with Residue 174 in the Hsd state is favored over that in the Hse state.