The Study Of Interaction Entropy Method In Selecting The Native Structure And Studying The Binding Mechanism Of Protein-Ligand System

In the research and development of new drugs,theoretical and computational studies play an increasingly important role in discriminating native and decoy structures by their binding free energies.Predicting the binding free energy using the molecular mechanics/Poisson–Boltzmann?Generalized Born?surface area?MM/PB?GB?SA?methods to identify the native structure as the lowest-energy conformation is more theoretically rigorous than most scoring functions,but the main challenge of this method is the calculation of the entropic contribution.In this study,we add the entropic contribution to the MM/PBSA and two MM/GBSA(GB^HCTCT and GB^OBC1)models using the interaction entropy?IE?method.We then systemically evaluate the performance of these methods in recognizing the native structures by predicting the binding affinities of 176 protein–ligand and protein–protein systems of the Bcl-2 family.By calculating a series of statistical metrics,sensitivity,specificity,accuracy,Matthews correlation coefficient,the G-mean,and the receiver operating characteristic?ROC?curve,we find that the ability to discern the native structure from a decoy ensemble is improved significantly by the modification of the binding free energy using the IE method in both protein–ligand and protein–protein systems.Furthermore,the maximum area under the ROC curve?AUC?is 0.97,which is obtained by the GB^HCTCT model combined with the IE method,indicating that this method has the best performance.The largest improvement occurs in the PB method,with a change in the AUC of0.32.The modification of the energy is more obvious for protein–protein interactions than for protein–ligand interactions.This study indicates the effectiveness of the IE method in successfully recognizing the native structure,which is critical in rational drug design.In addition,two groups of ten modified ligand systems,with modified P3 and P2 side chains,are used to study the binding mechanism with thrombin.Experimental results show that ligand side chains enhance the binding affinity.The binding free energy obtained from the polarized protein-specific charge?PPC?force field combined with the newly developed IE method is consistent with the experimental values with a high correlation coefficient.On the contrary,poor correlation is obtained using the traditional normal mode?Nmode?method for calculating the entropy change.Furthermore,binding free energy and hot-spot residue energy are decomposed,and the common hot-spot residues in the two groups of systems are Trp50,Leu96,Ile179,Asp199,Cyx201,Ser226,Trp227,Gly228,and Gly230.The electrostatic and van der Waals interaction energies are found to be the main contributors in the binding energy difference.CH–?and CH–CH interactions of Leu96 ligands are significantly related to the energy change due to the modified side chain,and the hydrogen bond between Asp199 and ligand provides a strong electrostatic interaction,contributing to the binding free energy.Investigating the B-factor,principal component,and binding pocket also explains the change in the binding affinity caused by the modified side chains in ligands from the viewpoint of conformational change.This study demonstrates that the new IE method is superior to the Nmode method in predicting binding free energy and emphasizes the importance of electronic polarization in molecular dynamics simulation.Moreover,from the viewpoint of energy and structure analysis,this study reveals the origin of the change in binding free energy in modified ligands with different binding sites.