MD Simulation And Binding Free Energy Calculation For VEGFR2 And RNA Binding Protein Systems

In recent years,with the marketing of anti-angiogenesis drugs such as Lenvatinib,Sorafenib and Sunitinib,it has been shown that anti-angiogenesis inhibitors have become an important direction for the development of new anti-cancer drugs.VEGFR2 is an important receptor for regulating angiogenesis and it has become an important target of anti-tumor therapy.Lenvatinib,Sorafenib and Sunitinib are targeted anti-cancer drugs on the market,and one of their target is VEGFR2.There are two different conformations of VEGFR2,viz,the active conformation(DFG-in conformation)and the inactive conformation(DFG-out conformation),and the two different conformations could be used to design inhibitorss.For example,Lenvatinib binds to DFG-in conformation,and Sorafenib/Sunitinib bind to DFG-out conformation.To further understand the structural determinasts of drug molecules(Lenvatinib,Sorafenib and Sunitinib)and their dynamic interaciton with VEGFR2.In the second chapter of this paper,molecular docking,MD simulation,and MM-GBSA are used to study binding mechanism between drugs and VEGFR2.This study not only shows the key residues in the binding process,but also suggestes that the Van der Waals interaction is the key driving force in the binding process.The result of free energy decomposition showed that residues L840,V848,A866,E885,L889,v889,V899,V916,F918,C919,L1035,C1045,D1046,and F1047 are key residues for inhibitor Lenvatinib/Sorafenib binding VEGFR2.Residues L840,V848 and E917 are key residues that for Sunitinib binding VEGFR2.Proteins and RNA are two important functional macromolecules in organisms.Their interactions involve basic life activities including transcription and translation.Therefore,an accurate understanding of the binding mechanism between proteins and nucleic acids will not only help to deepen the understanding of biological functions,but also design novel drug molecules for their interactions.MM-GBSA,as a widely used binding free energy calculation method,is less accurate in protein-nucleic acid system than in protein-inhibitor system.Therefore,in order to improve the accurancy of the MM-GBSA calculation method for protein-RNA system,a new Nwat-MMGBSA method was developed in the third chapter.Through the study of various protein-RNA systems,we found that the addition of water molecules could effectively improve the accurancy of calculation.Further analysis shows that the accuracy of binding free energy calculation is less affected by the simulation time of MD.