Molecular Dynamics Studies Of Vinblastine And Its Vindoline Dimer Interacting With α,β-Tubuline

Microtubules play an important role in cell mitosis and other aspects,and disrupting the dynamic balance of microtubules can stop cell mitosis and prevent cell proliferation.Vinblastine is a depolymerizing agent that inhibits tubulin polymerization and is highly cytotoxic to cancer cells.Studying the mechanism of interaction between vinblastine with tubulin can provide a better understanding for nature of vinblastine that is high cytotoxicity to cancer cells.Based on their interaction mechanisms,it is possible to develop an anti-cancer drug that is highly effective,less toxic,and economical for cancer cells.In this dissertation,Dock 6 program was used to obtain vinblastine-tubulin and vindoline dimer-tubulin binary complexes.The binary complex protein was subjected to molecular dynamics simulation using the Gromacs 4.5.3 program.The simulated steps were 50,000,000,and each step was 2 femtoseconds.The simulation time was 100 ns.Based on the atomic-scale resolution binary complex protein structure obtained by molecular dynamics simulation,the interactions of vinblastine and wendolin dimer molecules with single amino acid residues were calculated using the MP2/6-31G（d,p）calculation method,and the binding energy was obtained.Based on the binding energy,the active site amino acids of vinblastine（VLB）and vindoline dimer（DVB）interacting withα,β-tubulin（1Z2B）were studied.The results showed that there are 20 active residues for the DVB molecule:β-Asp179、β-Glu207、β-Tyr210、β-Thr221、β-Phe214、β-Pro222、β-Tyr224、β-Leu227、α-Asn249、α-Arg308、α-Lys326、α-Asn329、α-Ala333、α-Thr334、α-Lys336、α-Lys338、α-Arg339、α-Ser340、α-Thr349、α-Phe351.There are 16 active residues for the VLB molecule:β-Asp179、β-Glu207、β-Tyr210、β-Thr221、β-Phe214、β-Pro222、β-Tyr224、β-Leu227、α-Asn249、α-Arg308、α-Lys326、α-Asn329、α-Ala333、α-Thr334、α-Lys336、α-Lys338、α-Arg339、α-Ser340、α-Thr349、α-Phe3513.Among them,β-Asp179、β-Tyr210、β-Pro222、β-Tyr224、α-Lys326、α-Asn329 andα-Phe351 are common active residues for the VLB and DVB molecules.The total binding energy of the interaction between vinblastine withα,β-tubulin was-225.34 kJ·mol^-1,and the total binding energy of DVB withα,β-tubulin interaction was-250.98 kJ·mol^-1.The data shows that DVB interacts more strongly withα,β-tubulin.Based on the optimized structure of vinblastine and vindoline dimer withα,β-tubulin,the PMF and sample methods were used to study the molecular dynamics of the depolymerization trajectory and free energy ofα,β-tubulin depolymerization.The free energy required for the depolymerization of pureα,β-tubulin is 195.37 kJ·mol^-1.When there is a VLB molecule at the interface betweenα-tubulin andβ-tubulin,α,β-microtubule depolymerization requires a free energy of 217.85 kJ·mol^-1;when DVB molecules are present at the interface betweenα-tubulin andβ-tubulin,theα,β-tubulin depolymerization requires 250.10 kJ·mol^-1.The data indicate that pureα,β-tubulin depolymerization requires minimal energy.When there is a small molecule of drug at the tubulin interface,the energy required for the depolymerization ofα,β-tubulin is increased,and the effect of the vindoline dimer on the depolymerization of the protein is greater than that of the vinblastine molecule,and depolymerization needs more free energy.The data demonstrate that vinblastine compounds can increase the free energy ofα,β-tubulin depolymerization,show the anti-depolymerization properties as an inhibitor of tubulin depolymerization,and demonstrate the cytotoxic nature of cancer cells.Moreover,vindoline dimer has stronger inhibition of tubulin depolymerization than vinblastine,and should be more cytotoxic to cancer cells.Therefore,the newly designed wendolin dimer molecule has potential for development and application.