Molecular Mechanisms of Disease-Causing Missense Mutations |
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Authors: | Shannon Stefl Hafumi Nishi Marharyta Petukh Anna R. Panchenko Emil Alexov |
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Affiliation: | 1 Computational Biophysics and Bioinformatics, Department of Physics, Clemson University, Clemson, SC 29634, USA;2 National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health, Bethesda, MD 20894, USA |
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Abstract: | Genetic variations resulting in a change of amino acid sequence can have a dramatic effect on stability, hydrogen bond network, conformational dynamics, activity and many other physiologically important properties of proteins. The substitutions of only one residue in a protein sequence, so-called missense mutations, can be related to many pathological conditions and may influence susceptibility to disease and drug treatment. The plausible effects of missense mutations range from affecting the macromolecular stability to perturbing macromolecular interactions and cellular localization. Here we review the individual cases and genome-wide studies that illustrate the association between missense mutations and diseases. In addition, we emphasize that the molecular mechanisms of effects of mutations should be revealed in order to understand the disease origin. Finally, we report the current state-of-the-art methodologies that predict the effects of mutations on protein stability, the hydrogen bond network, pH dependence, conformational dynamics and protein function. |
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Keywords: | SNP, single nucleotide polymorphism HDL, high-density lipoprotein 3D, three-dimensional SVM, support vector machine MD, molecular dynamics RTK, receptor tyrosine kinase |
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