The Impact Of Dielectric Constant For The Affinity And The Entropic Effect To The Cooperativity In Streptavidin-biotin Binding Investigated By Interaction Entropy Method

At present,the accurate prediction of binding free energy of protein-ligand complexes has become the research direction of scientists.Accurate prediction of binding free energy of protein-ligand complexes can not only help to explore its binding mechanism,but also contribute to study the drug screening and the origin of cooperativity.However,due to some limitations of conditions and methods,such as the inconsistency between the setting of dielectric constant in simulated environment and the actual dielectric constant,and the inefficiency of the entropy prediction method,the accuracy and efficiency of the binding free energy prediction are poor nowadays.The purpose of this study is to explore the effects of dielectric constant and entropy change on binding free energy by using a new interaction entropy(IE)method,and to explain the interaction mechanism and cooperativity from the perspective of molecular mechanism.Nowadays,the calculated binding free energy obtained using the molecular mechanics/Poisson-Boltzmann(Generalized-Born)surface area(MM/PB(GB)SA)method is overestimated due to the lack of knowledge of suitable interior dielectric constants in the simulation on the interaction of Human Immunodeficiency Virus(HIV-1)protease systems with inhibitors.Therefore,the impact of different values of the interior dielectric constant and the entropic contribution when using the MM/PB(GB)SA method to calculate the binding free energy was systemically evaluated.Our results show that the use of higher interior dielectric constants(1.4–2.0)can clearly improve the predictive accuracy of the MM/PBSA and MM/GBSA methods,and computational errors are significantly reduced by including the effects of electronic polarization and using a new highly efficient interaction entropy(IE)method to calculate the entropic contribution.The suitable range for the interior dielectric constant is 1.4–1.6 for the MM/PBSA method;within this range,the correlation coefficient fluctuates around 0.84,and the mean absolute error fluctuates around 2 kcal/mol.Similarly,an interior dielectric constant of 1.8-2.0 produces a correlation coefficient of approximately 0.76 when using the MM/GBSA method.In addition,the entropic contribution of each individual residue was further calculated using the IE method to predict hot-spot residues,and the detailed binding mecha nisms underlying the interactions of the HIV-1 protease,its inhibitors,and bridging water molecules were investigated.In this study,the use of a higher interior dielec tric constant and the IE method can improve the calculation accuracy of the HIV-1 system.Molecular dynamics(MD)simulations are performed to explore the origin of cooperativity in the binding affinities of four streptavidin-biotin systems(wild type,two single mutations and one double mutation)employing polarized protein-specific charge(PPC).Experiment determined that the loss of binding free energy in double mutation system is greater than sum of two single mutation systems,indicating cooperativity between two mutated residues.Further,the cooperativity is mainly a result of entropic effect.In this study,the recently developed interaction entropy(IE)method is employed to compute entropic contribution and result is excellent consistent with experimental observation.Furthermore,the IE method allows us to obtain residue specific entropy contribution toward binding affinity approximately.Our study identified that six residues forming hydrogen bonds with the biotin provide the dominant contribution to the binding cooperativity.In addition,three additional residues are also found to contribute to the binding cooperativity.The present study provides significant molecular insight into the binding cooperativity of streptavidin-biotin complex.