Source: http://www.dynameomics.org/external/Snps/index.aspx
Timestamp: 2019-04-20 06:16:24+00:00

Document:
We have created a SNP database that contains wildtype and SNP protein simulations. Our aim is to facilitate analysis of SNP pathologies and how they relate to the structure, stability, function, and dynamics of the protein. Our SNP database currently contains approximately 200 single-point mutations and their counterpart wildtype proteins. In total, 31 proteins are represented. A subset of these proteins and their associated diseases are listed below in Table 1.
Table 1: A subset of the disease-related proteins present in the Dynameomics SNP database.
Our simulations have provided insights into the structural mechanisms behind the protein destabilization of several SNP mutants. One common theme is the structural disruption of a protein at a location distant from the point of the SNP mutation. The simulation of the V108M mutation in catechol O-methyltransferase, for example, reveals a 16 Å separation between the amino acid substitution point and the structurally disrupted enzyme active site [1, 2]. The crystal structures of this protein with bound cofactor and substrate analog are very similar and do not show these large differences . Other SNP simulations such as histamine N-methyltransferase , thiopurine S-methyltransferase , DJ-1 , and the DNA glycosylase/β-lyase hOgg1  have also shown this long-range disruptive behavior.
Rutherford K., Bennion B.J., Parson W.W., and Daggett V. The 108M Polymorph of Human Catechol O-Methyltransferase Is Prone to Deformation at Physiological Temperatures. Biochemistry 45: 2178-2188, 2006.
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.
Rutherford K., Alphandéry E., McMillan A., Daggett V., and Parson W.W. The V108M mutation decreases the structural stability of catechol O-methyltransferase. Biochimica et Biophysica Acta 1784: 1098-1105, 2008.
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.
Rutherford K. and Daggett V. Four Human Thiopurine S-Methyltransferase Alleles Severely Affect Protein Structure and Dynamics. Journal of Molecular Biology 379: 803-814, 2008.
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.
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.
Calhoun S. and Daggett V. Structural effects of the L145Q, V157F, and R282W cancer-associated mutations in the p53 DNA-binding core domain. Biochemistry 50:5345-5353, 2011.
Wang, D., McCully, M.E., Luo, Z., McMichael, J., Tu, A., Daggett, V., Regnier, M. Structural and function consequences of cardiac tropinin C L57Q and I61Q Ca2+-desensitizing variants. Archives of Biochemistry and Biophysics, 535: 68-75, 2013.

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