The Interaction Entropy Method Was Used To Study The Effects Of Electrostatic Polarization And The Binding Affinity Of Bridge Water Molecules On CDK2-ligand Binding Affinity

As a member of homologous protein family,protein kinases(PKs)participates in lots of physiological and biochemical processes,for instance,which plays a significant role in the growth,metabolism,differentiation and apoptosis of cells.Belonging to a category of PKs family,Cyclindependent kinases(CDKs)are employed to regulate and control the processes of cell proliferation,neurologic function,and transcription.Structural mutation and overexpression of CDKs lead to cell cancerization.Therefore,more and more researchers pay special attention to investigating the structures and functions of CDKs.As is universally known to all,loss control of cell cycle brings about immortal or malignant cell proliferation,and then leads to lead to cell cancerization,and causes cancers ultimately.Cyclin,CDKs and CDKs' inhibitors monitor and manage the cell cycle,jointly.As a well-known member of CDKs,combined with Cyclin A and E,Cyclin-dependent kinase 2(CDK2)mainly takes part in controlling the transition from G1 to S phase,S phase and the transition from S to G2 phase of cell cycle.If the transition from G1 to S phase is incontrollable,the process of cell cycle will go straight into S or M phase.Therefore,CDK2 is a promising target for the treatment of cancer,and its inhibitors are widely used in the modification and design of anticancer drugs.At present,we can obtain a lot of crystal structures of CDKs and their inhibitors from the Protein Data Bank(PDB),which is very helpful to our study.However,there are some defects and deficiencies in the research of this system:1)In the process of molecular dynamics simulation(MD simulation),the accuracy of the force field parameters has a great of influence on the precision of simulation processes and results.However,in the existing force fields,such as AMBER,CHARMM,and so on,the mean field method is used to fit the atomic partial charges,and the polarization effect of the biological molecules,water molecules and ions is neglected.Many researches have proved that the polarization effect has a significant influence on the simulation results.Therefore,we have used a new type of charge fitting scheme,polarized protein specific charge(PPC)fitting scheme.In the process of fitting atomic partial charges,we fully consider the polarization effect between the biomolecules and their surrounding environment.In the process of simulation,we can get a more stable and reliable conformation,and get more accurate simulation results.2)In terms of the system,many studies have only studied the mechanism of the interaction between CDK2 and its inhibitors,and ignored the regulatory role of bridging water molecules to monitor the complexes.By observing most crystal structures of CDK2 and its inhibitors,a water molecule can not only form hydrogen bond with Asp145 of the protein,but also form hydrogen bond with the inhibitor(we called Wat145),play the "bridge" role,and regulate the hydrogen bonds network between them.Wat145 is present in most of the crystal structures,and in many studies,its role is often neglected.Therefore,in this paper,we focus on the effect of Wat145 on the hydrogen bond network between proteins and ligands,and the contribution of Wat145 to the binding free energy.Based on the above results,to displace the Wat145 or not is to be predicted in the modification and design of anticancer drugs,and the results are consistent with the conclusions of the Essex study group.3)When using the traditional MM/PBSA method to calculate the binding free energy,the entropy change of Normal mode(Nmode)analysis is very time consuming.Considering the efficiency problem,we can only reduce the sampling,which will lead to the accuracy of the simulation results.In view of the above problems,a more simple and efficient method for calculating the entropy change,namely the interaction entropy(IE)method,is employed by a rigorous mathematical derivation according to the most basic thermodynamics statistical physics formulas.The method only needs to know the interaction energy and its fluctuation between the protein and ligand,and it can calculate the entropy change efficiently without the need of additional and complex calculation.Because of the high efficiency of this method,we can make full sampling,and then make the simulation results more accurate.Our results reveal that in consideration of the Wat145,the calculated binding free energy has a significantly linear correlation with experimental result with the correlation coefficient of 0.98 under PPC combined IE method,and the rank of computational binding free energies is significantly consistent with the rank of experimental values.The contribution of Wat145 to the binding free energy is different in different complexes,depending on their binding environment.The above conclusions provide a good theoretical basis for the design and modification of anticancer drugs,which has a strong significance.