Title: Structural assessment of the effects of Amino Acid Substitutions on protein stability and protein–protein interaction

Authors: Shaolei Teng, Anand K. Srivastava, Charles E. Schwartz, Emil Alexov, Liangjiang Wang

Addresses: Department of Genetics and Biochemistry, Clemson University, Clemson, SC 29634, USA. ' J.C. Self Research Institute of Human Genetics, Greenwood Genetic Center, Greenwood, SC 29646, USA. ' J.C. Self Research Institute of Human Genetics, Greenwood Genetic Center, Greenwood, SC 29646, USA. ' Department of Physics and Astronomy, Clemson University, Clemson, SC 29634, USA. ' Department of Genetics and Biochemistry, Clemson University, Clemson, SC 29634, USA

Abstract: A structure-based approach is described for predicting the effects of amino acid substitutions on protein function. Structures were predicted using a homology modelling method. Folding and binding energy differences between wild-type and mutant structures were computed to quantitatively assess the effects of amino acid substitutions on protein stability and protein–protein interaction, respectively. We demonstrated that pathogenic mutations at the interaction interface could affect binding energy and destabilise protein complex, whereas mutations at the non-interface might reduce folding energy and destabilise monomer structure. The results suggest that the structure-based analysis can provide useful information for understanding the molecular mechanisms of diseases.

Keywords: AASs; amino acid substitutions; homology modelling; folding energy; binding energy; protein stability; protein–protein interaction; protein function; pathogenic mutations; molecular mechanisms; diseases.

DOI: 10.1504/IJCBDD.2010.038396

International Journal of Computational Biology and Drug Design, 2010 Vol.3 No.4, pp.334 - 349

Published online: 04 Feb 2011 *

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