Theoretical Studies On Important Organic Chemical Reactions And Protein-Ligand Interaction

With the development of computer technology and scientific method,the scope of theoretical computational chemistry and molecular simulation has been expanded a lot.It can not only provide systematic explanation and establish a correct micro-mechanism for some important biochemical processes,but also can provide valuable information for biomolecule optimization,the regulation of biomolecular function by small molecule,and structure-reactivity relationship of biomolecules.In this paper,a series of important organic chemical reactions and the interaction of protein and ligand have been studied through the theoretical computational method and molecular simulation.The DFT methods,multi-scale simulation and free energy calculation methods have been applied to the corresponding studies.In chapter two,the selectivities in C-H oxidations of a variety of compounds by DMDO have been explored with density functional theory.There is a linear Evans-Polanyi-type correlation for saturated substrates.Activation energies correlate with reaction energies or,equivalently,BDEs(?H^?_sat=0.91*BDE-67.8).Unsaturated compounds,such as alkenes,aromatics,and carbonyls,exhibit a different correlation for allylic and benzylic C-H bonds(?H^?_unsat=0.35*BDE-13.1).Bernasconi's Principle of Non-Perfect Synchronization?NPS?is found to operate here.The origins of this phenomenon were analyzed by a Distortion/Interaction model.Computations indicate early transition states for H-abstractions from allylic and benzylic C-H bonds,but later transition states for the saturated.The reactivities are mainly modulated by the distortion energy and the degree of dissociation of the C-H bond.While the increase in barrier with higher BDE is not unexpected from the Evans-Polanyi relationship,two separate correlations,one for saturated compounds,and one for unsaturated leading to delocalized radicals,were unexpected.In chapter three,a QM/QM'direct molecular dynamic study of a water-accelerated Diels-Alder reaction in aqueous solution is reported.Cyclopentadiene and methyl vinyl ketone are known to react faster in water than in nonpolar solvents.We have explored how polarization of water molecules afforded by PM3 influences the nature of the transition state,and the reaction dynamics.We compare the results with previous studies on QM/MM and QM/MM+3QM water simulations from our laboratory.Transition state sampling in vacuum PM3 water boxes indicates that the asynchronicity is 0.54???in QM/QM',as compared to 0.48???in QM/MM,and 0.54???in QM/MM+3QM water.The mean time gap between the formation of two C-C bonds is 19 fs for QM/QM',compared to 20 fs for QM/MM,and 25 fs for QM/MM+3QM water.The samplings and time gaps are qualitatively consistent,indicating that water polarization is not significant in sampling and dynamics of bonding changes.The dynamics of hydrogen bonding between reacting molecules and water molecules was also analyzed.From reactants to transition states,H-bond shortening is 0.4???by QM/QM',while only 0.15???for QM/MM and QM/MM+3QM water.From reactants to transition states,the mean value of the H-bond angle increases by 19°in QM/QM',but only 4°in QM/MM,and 10°in QM/MM+3QM water.These suggest that water polarization is essential for the correct representation of dynamical formation of hydrogen bonds in the transition state by water reorientation.QM/QM'overestimates the hydrogen bonding enhancement because of its underestimation of neutral hydrogen bonding within the reactants,a general deficiency of PM3.In chapter four,Previous experimental study measuring the binding affinities of biotin to the wild type streptavidin?WT?and three mutants?S45A,D128A and S45A/D128A double mutant?has shown that the loss of binding affinity from the double mutation is larger than the direct sum of those from two single mutations.The origin of this cooperativity has been investigated in this work through molecular dynamics simulations and the end-state free energy method using the polarized protein-specific charge.The results show that this cooperativity comes from both the enthalpy and entropy contributions.The former contribution mainly comes from the alternations of solvation free energy.Decomposition analysis shows that the mutated residues nearly have no contributions to the cooperativity.Instead,N49 and S88,which are located at the entry of the binding pocket and interact with the carboxyl group of biotin,make the dominant contribution among all the residues in the first binding shell around biotin.Quinazolines bind to p38?mitogen-activated protein?MAP?kinase via a tightly bound water molecule.It remains unclear whether this water molecule should be displaced in order to improve binding affinity or specificity of new ligands.In this work,we proposed a method that can predict the binding affinity of ligands that displace this water molecule via a decomposition of the protein-ligand binding process into a series of subprocesses.The free energy change associated with each subprocess can be calculated using either the multi-state Bennett Acceptance Ratio?MBAR?or the thermodynamic perturbation?TP?estimator.This method bypasses the simulation utilizing a hard-wall potential,which prevents the entry of other water molecules into the pocket when the original water molecule was decoupled from its environment in an alchemical pathway.Furthermore,with the assistance of the Molecular Mechanics/Poisson-Boltzmann Surface Area?MM/PBSA?method,the binding affinities of new ligands can be predicted quickly.The results show that displacing this water molecule by replacing the nitrogen at position-3 of4-Anilinoquinazolines with a polar cyano group?-C-CN?,which was used to optimize the EGFR inhibitor,is feasible for the association with p38?MAP kinase.Besides,we also discovered that-CH₂OH and-CH₂Cl substituents are potential candidates with competitive affinities.