New Method For Accurate Theoretical Calculation Of Protein-ligand Binding Free Energy

Drug molecules often interfere with the function of proteins by binding to target proteins,which can treat diseases.The important physiological and pharmacological functions of many proteins are manifested by their interaction with small molecules.For example,the interaction between an enzyme and a substrate reflects the catalytic function of an enzyme.The activity of many drugs or other biologically active molecules is manifested through the interaction with the biomolecules of the receptor,so the binding affinity of the drug to the receptor is directly related to the activity of the drug.X-ray crystallography or nuclear magnetic resonance spectroscopy can obtain the atomic resolution structure of protein-ligand complex,provides a chemical basis for understanding protein-ligand interactions.It can be used as a basis for designing smallmolecule drugs for treating diseases.In structure-based drug design,it is necessary to use the three-dimensional atomic structure of the complex to calculate the binding free energy of a large number of proposed ligands to a given target protein.In terms of accuracy in evaluating the protein-ligand binding,free energy perturbation(FEP)and thermodynamic integration(TI)are considered high-end methods taht are theoreticaly rigorous but prohibitively expensive when evaluation of a large number of priteinligand complexes,suah as in drug screnning.At the low end,the empirical scoring function is widely used for fast estimation of protein-ligand binding affinities in large numbers because of their higher efficiency.However,using a simple empirical scoring function to evaluate the binding free energy is usually not very reliable.There is Poisson-Boltzmann surface area(MM / PBSA)method between the two,and the accuracy is usually between FEP and the empirical scoring function is a common method for calculating protein-ligand binding affinity.The first job of this paper,PBSA_E,a new free energy estimator based on the molecular mechanics/Poisson-Boltzmann surface area(MM/PBSA)descriptors,has been developed.This free energy estimator was optimized using high-quality experimental data from a training set consisting of 145 protein-ligand complexes.The method was validated on two separate test sets containing 121 and 130 complexes.Comparison of the binding affinities predicted using the present method with those obtained using three popular scoring functions,i.e.,GlideXP,GlideSP,and SYBYL_F,demonstrated that the PBSA_E method is more accurate.This new energy estimator requires a MM/PBSA calculation of the protein-ligand binding energy for a single complex configuration,which is typically obtained by optimizing the crystal structure,save time for MD simulation.The present study shows that PBSA_E has the potential to become a robust tool for more reliable estimation of protein-ligand binding affinity in structure-based drug design.In the traditional MM/PBSA calculation combined with protein-ligand binding free energy,the widely used method of entropy estimation is to use the normal mode.However,this method is not only a theoretical approximation but is computationally expensive and inaccurate.In the second job of this paper,we present a new interaction entropy method which is theoretically rigorous,computationally efficient,and numerically reliable for calculating entropic contribution to free energy in protein-ligand binding and other interaction processes.Drastically different from the widely employed but extremely expensive normal mode method for calculating entropy change in protein-ligand binding,the new method calculates the entropic component(interaction entropy or-T?S)of the binding free energy directly from molecular dynamics simulation without any extra computational cost.Extensive study of over a dozen randomly selected protein-ligand binding systems demonstrated that this interaction entropy method is both computationally efficient and numerically reliable and is vastly superior to the standard normal mode approach.This interaction entropy paradigm introduces a novel and intuitive conceptual understanding of the entropic effect in protein-ligand binding and other general interaction systems as well as a practical method for highly efficient calculation of this effect.In protein-ligand binding,only a few residues contribute significantly to the ligand binding.Quantitative characterization of binding free energies of specific residues in protein-ligand binding is extremely useful in our understanding of drug resistance and rational drug design.In this paper,we present an alanine scanning approach combined with an efficient interaction entropy method to compute residue-specific protein-ligand binding free energies in protein-drug binding.In the current approach,the entropic components in the free energies of all residues binding to the ligand are explicitly computed from just a single trajectory MD simulation by using the interaction entropy method.In this approach the entropic contribution to binding free energy is determined from fluctuations of individual residue-ligand interaction energies contained in MD trajectory.The calculated residue-specific binding free energies give relative values between those for ligand binding to the wild type protein and those to the mutants when specific results mutated to alanine.Computational study for the binding of two classes of drugs(first and second generation drugs)to target protein ALK and its mutant was performed.Important or hot spot residues with large contributions to the total binding energy are quantitatively characterized and the mutation effect for the loss of binding affinity for the first generation drug is explained.Finally,it is very interesting to note that the sum of those individual residue-specific binding free energies are in quite good agreement with the experimentally measured total binding free energies for this proteinligand system.