Studies On The Interactional Mechanisms Of Several Important Diseases’s Proteins And Their Inhibitors By Molecular Dynamics Simulations

In recent years, protein conformation has been a research hotspot for human diseases. The conformantional changes of important proteins have initiated a variety of diseases. Today, with the developments of biophysics, biological medicine and information science, a lot of crystal structures of protein-inhibitor complex have been resolved. Meanwhile, the curative effect of the drug has been a hot topic in scientific research and medical treatment. Therefore, how to improve the therapeutic effect of drugs is on the agenda. Our research team is committed to explore interactional mechanisms of inhibitors and several important proteins related with diseases by molecular dynamics simulations.We analysis protein conformantional changes and binding free energy of protein-inhibitor complex. On the basis of the datas above, we put forward the interactional mechanisms at the atomic level. The understanding of interactional mechanisms of inhibitors and proteins is of great important, as it will have a profound impact on the future design of more potent and effective drugs.1. Insights into resistance mechanism of macrolide antibiotic Erythromycin against the Macrolide biosensor protein MphR(A) by molecular dynamics simulations and binding free energy calculations.Macrolide biosensor protein MphR(A) has been known as a key regulatory protein in metabolite sensing and exogenous control of gene expression.MphR(A) binds to macrolide antibiotic Erythromycin and releases the operator, thus activates transcription of the mphA gene and initiates Erythromycin resistance.The two mutant amino acid residues (V66L and V126L) might potentially disrupt Erythromycin binding to MphR(A). In our work, the binding of macrolide antibiotic Erythromycin (Ery) to wild-type(Wt) and double (V66L/V126L) mutant Macrolide biosensor protein MphR(A) was investigated with all-atom molecular dynamics (MD) simulations and MM-GBSA calculation. For both the apo MphR(A) protein and complex Wt-MphR(A)-Ery, many intriguing effects due to double mutant V66L/V126L are observed. In the case of Erythromycin, Helix I is a right-hand alpla helix in Wt-MphR(A)-Ery, whereas the activated right hand alpha helix is broken down in double mutant-V66L/V126L-MphR(A)-Ery. The present results also show that the double mutant V66L/V126L decreases the binding affinity of V66L/V126L-MphR(A) protein to Erythromycin, resulting in the block of Erythromycin resistance. The energy decomposition analysis suggests that the decrease of the binding for the double mutant V66L/V126L-MphR(A)-Ery can be mainly attributed to the increase in electrostatic energy.The V66L/V126L mutant directly decreases the binding affinity.The residues Leu66, Argl22, and Thr154 increase the binding affinity of V66L/V126L-MphR(A) to Erythromycin. Another two residues Tyr103 and Hie147 are main binding energy contributor in the Wt-MphR(A)-Ery complex. The current study can give useful insights into the nature of mutational effect, the mechanism of blocking drug resistance at the atomic level and the difference in binding affinity for Erythromycin in double (V66L/V126L) mutant MphR(A) variant supports the future design of more potent and effective macrolide antibiotics.2. The Binding Mechanism of a Novel Nicotinamide Isostere Inhibiting with TNKSs:A Molecular Dynamic SimulationTankyrases (TNKSs), a member of human Poly (ADP-ribose) polymerase (PARP) protein superfamily, plays a key role in regulation of cell proliferation. Among the representative proteins of the poly ADP-ribose polymerases family, we find that the inhibitors have high selectivity for Tankyrase1 (TNKS1).The specific binding modes are investigated between the TNKS1 protein and nicotinamide isostere (ISX) which makes as an inhibitor of TNKS1. On the basis of the calculated results of Molecular Dynamics (MD) simulations, the influence of inhibitors to the conformational flexibility of TNKS1 is discussed and the conformational twist of the peptide Ile1228-Glyl229-Gly1230 is explored. One finds that the lead compound XAV939 binding drives the peptide Ile1228-Glyl229-Gly1230 to form a helical conformation while the ISX binding can drive the peptide to form a turn structure. The calculated results exhibit that the important hydrogen bonds of residue Tyr1203 and WAT1551 with respective XAV939 and ISX stabilize the complexes, and that the electrostatic interactions in TNKS1-XAV939 and van der Waals energy in TNKS1-ISX system are main driving forces for affinity. Moreover, the stabilities of these complexes are estimated by molecular dynamics simulations and free energy calculations; a good agreement with experimental results is reached. According to results of the decomposition of binding free energy, it is obvious that the residues Try1224 and Lys1220 make the most favorable contributions to the binding free energy in respective ISX-and XAV939 complexes. Generally, the obtained results are useful for studying the binding mechanisms of protein and inhibitors and for designing potent inhibitors.