Thermodynamic Mechanism Of Protein Folding And Docking Based On Entropy-entralpy Compensation

The problem of protein folding and protein docking has been the central concern in molecular and structural biology.Proteins and their products are the basis of life on earth.Known biochemical reactions and life phenomena are completed by proteins.Hundreds of billions of different proteins exist in organisms on Earth,and the biological function and activity of each protein is expressed through its characteristic 3D shape.The solutions to protein folding and docking problems will promote the rapid development of molecular biology,structural biology,biophysics,biochemistry,pathology,genetics and pharmacology,and have a wide and far-reaching impact.Hydrogen bonds play an important role in maintaining the stability of protein molecules.In this study,we found that during protein folding and docking,the side chains of amino acid residues break away from the water molecules in the surrounding environment to form hydrogen bonds with the side chains of other amino acid residues with weak bonding ability.This process is driven by the entropy increase caused by the hydrophobic interaction between the side chains of amino acid residues.The hydrophobic collapse and agglomeration between the side chains of amino acid residues will cause the low-entropy water molecules in the hydration layer around them to enter the aqueous solution environment,resulting in an increase in system entropy.This increase in entropy compensates for the increase in system enthalpy caused by the formation of hydrogen bonds within and between protein molecules,resulting in a negative free energy change of the system.Therefore,this entropy-increasing phenomenon drives the spontaneous and precise process of protein folding and docking,which is the thermodynamic mechanism of protein folding and docking based on entropy-enthalpy compensation revealed in this work.The protein folding process starts from the universal initial thermodynamic metastable state of the unfolded protein molecular chain.The instability of this state and the hydrophobic collapse drive the protein folding process.In this study,we found that the water solvent force in the driving force of protein folding can shrink the hydrophobic surface of protein,expand the hydrophilic surface of protein,and cause many fragments of protein chain to collapse into local hydrophobic groups.This mechanism reveals that entropy-enthalpy compensation drives protein folding process.The contraction of the hydrophobic surface of the protein molecule will further reduce the conformational Gibbs free energy and drive the protein folding process forward.By evaluating the measured hydrophobic interactions between the side chains of adjacent residues in proteins,the folding code of the secondary structure of proteins was summarized and the prediction method of the tertiary structure was proposed.The formation of quaternary protein structure and the docking and binding process of proteins are equivalent.In this study,we verified the dominant role of hydrophobic interaction in protein docking and found that there are large hydrophobic groups at the docking sites of proteins and participate in the hydrophobic collapse between the two proteins.In this paper,molecular dynamics simulations show that a new penetrating hydration layer is formed on the outside of the protein docking complex after the protein docking process is completed.The hydrophobic collapse at the protein docking surface causes a large number of low-entropy water molecules in the surrounding hydration layer to enter the aqueous solution environment.In this process,the entropy increase generated by the system is sufficient to compensate the enthalpy increase caused by the side chains of hydrophilic residues forming hydrogen bonds at the protein docking surface,and the system free energy change is negative,which drives the protein docking process forward.This is the thermodynamic mechanism of protein docking based on entropy-enthalpy compensation revealed in this paper.Based on the thermodynamic mechanism of protein docking,this paper proposes a method to evaluate the docking affinity of proteins by calculating the hydrophobic collapse area at the docking surface of protein molecules.According to this method,this paper reveals the reason why SARS-Co V-2 has much higher infectivity than SARS virus.In addition,based on the thermodynamic mechanism of protein docking,a method for predicting protein docking complexes and a formula for calculating the binding free energy of protein docking are proposed.Here,we investigated the effect of amino acid mutations on protein docking binding affinity.Taking the effect of amino acid mutations in SARS-Co V-2 variant strains on the infectivity of SARS-Co V-2 as an example,we analyzed the receptor-binding domain(RBD)of SARS-Co V-2 spike protein(S),ACE2 protein and the hydrophobic interaction area of different antibodies to quantify the hydrophobic attraction and hydrophilic repulsion caused by amino acid mutations.By analyzing the entropy-enthalpy compensation relationship at the docking binding sites of proteins,it was found that the original hydrophobic attraction and hydrophilic repulsion were changed by the amino acid mutation at the docking binding sites,which changed the docking binding affinity of proteins.In this study,a large number of data were used to verify the thermodynamic mechanism of protein docking based on entropy-enthalpy compensation.The calculated docking affinity between the receptor-binding domain of SARS-Co V-2 spike protein and ACE2 protein was significantly higher than that of SARS virus,which was consistent with the objective fact that SARS-Co V-2 had significantly higher infectious ability than SARS virus.The thermodynamic mechanism of protein docking based on entropyenthalpy compensation was used to explain the phenomenon that the infectivity of SARSCo V-2 was significantly higher than that of SARS-Co V-2.In addition,the infectivity of SARS-Co V-2 variants is stronger than that of the native SARS-Co V-2.Among them,the Delta variant of SARS-Co V-2 can specifically reduce the docking binding affinity to nine antibody proteins,which is consistent with the phenomenon that SARS-Co V-2 Delta variant has the risk of breakthrough infection in vaccinated countries.