Single Nucleotide Polymorphisms

Primary sequence variants can have severe effects on protein stability and activity. However, polymorphic proteins are not always amenable to structural study due to increased degradation rates and aggregation. 3.1 million polymorphisms have been genotyped to date, many of which are strongly associated with disease. We use molecular dynamics simulations to study the structural and dynamic effects of these polymorphisms at atomic resolution. We are currently looking at common human disease-related polymorphisms within protein-fold families to identify polymorphic hotspots and common dynamic and structural features of these variants.

Relevant Publications

• Rutherford K., Parson W.W., and Daggett V. The Histamine N-Methyltransferase T105I Polymorphism Affects Active Site Structure and Dynamics. Biochemistry 47: 893-901, 2008. [DOI]
• Anderson P.C. and Daggett V. Molecular Basis for the Structural Instability of Human DJ-1 Induced by the L166P Mutation Associated with Parkinson's Disease. Biochemistry 47:9380-9393, 2008. [DOI]
• Rutherford K. and Daggett V. A Hotspot of Inactivation: The A22S and V108M Polymorphisms Individually Destabilize the Active Site Structure of Catechol O-Methyltransferase. Biochemistry, 48: 6450-6460, 2009. [DOI]
• Anderson P.C. and Daggett V. The R46Q, R131Q and R154H Polymorphs of Human DNA Glycosylase/β-Lyase hOgg1 Severely Distort the Active Site and DNA Recognition Site but do not Cause Unfolding. Journal of the American Chemical Society, 131: 9506-9515, 2009. [DOI]