Predicting the effect of point mutation on protein stability through conformational sampling and multiple dielectric model

Authors:

Tingting Han & Brian Dominy

PI/Advisor:

Dr. Brian Dominy

Program:

Chemistry (College of Engineering and Science)

Abstract:

Mutations could affect protein stability. This project aims to develop a method to calculate changes of the folding free energy of proteins upon single point mutations, and is achieved by applying conformational sampling and molecular dynamics simulation. The approach is applied to 150 mutants to estimate the effect of mutations on protein stability. The alternative protein conformations are generated via the program CONCOORD, and changes of protein stability are evaluated by the Molecular Mechanics/Poisson-Boltzmann Surface Area (MM/PBSA) method. The important role of conformational sampling is determined by comparing the methods of using a single minimized structure, a Concoord/minimized ensemble, and a Concoord/MD ensemble. Based on born radii of alpha carbons and the solvent accessible surface area of the amino acid, a protein is categorized into three regions: interior, partially exposed, and surface regions. Previous studies have shown that dielectric properties of different regions of proteins are different. In our current model, the optimal dielectric constant of the interior region is 4, and is lower than the outer part, where the value is 5 or 6. The three dielectric constant model results in a correlation coefficient of 0.71 and the standard deviation of 1.99kcal/mol between the computational and the experimental value.

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