Ligand binding and enzyme catalysis studied by molecular dynamics simulations

University dissertation from Uppsala : Acta Universitatis Upsaliensis

Abstract: Molecular dynamics simulations and free energy calculations can be applied to biomolecular systems to predict ligand binding affinities. Combined with hybrid quantum-classical potential energy surfaces, such computations can also be used to probe enzymatic catalysis mechanisms.For structure based drug design, an accurate method is needed for binding free energy prediction. A linear interaction energy (LIE) methods is presented, which calculates binding affinities from time averages of interaction potential energies between ligand and surroundings in simulations of the complex of ligand and receptor and of the ligand free in solution. The original version of the method assumes electrostatic linear response of the surrounding medium. The method is applied to inhibitors of HIV-1 proteinase, giving reasonable predictions of inhibition constants.Electrostatic linear response of the solvent to the solute electric field is valid for ionic species in aqueous solution, but specific deviations are found for electroneutral dipolar compounds. Statistical investigations using data from 18 complexes with four different proteins show that, in contrast to several other possible extensions to the method, these specific nonlinearities can be utilized to give a real improvement to the predictive power of the LIE method.Protein tyrosine phosphatases (PTPases) hydrolyze phosphate esters by formation of acovalent phosphoenzyme intermediate with a cysteine residue. This is followed by hydrolysis of the intermediate. Reaction potential surfaces of different possible steps in intermediate formation in the low molecular weight PTPase are modelled by the empirical valence bond (EVB) method. Molecular dynamics simulations and free energy perturbation calculations then yield reaction free energy profiles for these reactions steps. The activation of the cysteine 12 nucleophile is the object of a preliminary study. More extensive EVB investigations and substrate binding calculations yield a reaction free energy profile consistent with experimental findings for the formation of the phosphoenzyme intermediate. The calculations clearly indicate that the reaction complex is protonated and carries a total charge of (-2), and that the leaving group becomes protonated in concert with its expulsion.

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