SDM--a server for predicting effects of mutations on protein stability and malfunction

Abstract

The sheer volume of non-synonymous single nucleotide polymorphisms that have been generated in recent years from projects such as the Human Genome Project, the HapMap Project and Genome-Wide Association Studies means that it is not possible to characterize all mutations experimentally on the gene products, i.e. elucidate the effects of mutations on protein structure and function. However, automatic methods that can predict the effects of mutations will allow a reduced set of mutations to be studied. Site Directed Mutator (SDM) is a statistical potential energy function that uses environment-specific amino-acid substitution frequencies within homologous protein families to calculate a stability score, which is analogous to the free energy difference between the wild-type and mutant protein. Here, we present a web server for SDM (http://www-cryst.bioc.cam.ac.uk/~sdm/sdm.php), which has obtained more than 10 000 submissions since being online in April 2008. To run SDM, users must upload a wild-type structure and the position and amino acid type of the mutation. The results returned include information about the local structural environment of the wild-type and mutant residues, a stability score prediction and prediction of disease association. Additionally, the wild-type and mutant structures are displayed in a Jmol applet with the relevant residues highlighted.

RNA–DNA sequence differences in Saccharomyces cerevisiae

“…Figure 4 shows that the DNA (I319) and RNA (N319) forms of Vph1 have distinct folding properties (TM-score = 0.34, in contrast to >0.5 for control proteins with similar structures; P < 10 −6 ). Third, several RDDs are predicted to affect protein stabilities (Table 3; Worth et al 2011). For instance, for the transcription repressor Tup1, the RNA form (V459) is predicted to be more stable (ΔΔG = 1.02) than the DNAform (A459) (Worth et al 2011).…”

“…Third, several RDDs are predicted to affect protein stabilities (Table 3; Worth et al 2011). For instance, for the transcription repressor Tup1, the RNA form (V459) is predicted to be more stable (ΔΔG = 1.02) than the DNAform (A459) (Worth et al 2011). Next, we experimentally validated results from computational prediction and determined the functional consequences of RDDs by focusing on Tup1.…”

“…The TMscore (value 0-1 with 1 indicating the perfect match) was used to measure structural similarity between DNA-form and RNA-form models. Protein stability is predicted as previously published (Worth et al 2011). …”

Characterization of Wild-Type and Mutated RET Proto-Oncogene Associated with Familial Medullary Thyroid Cancer

“…For this purpose three different tools were used, including CUPSAT (Parthiban et al, 2006), FOLDx (Schymkowitz et al, 2005), MM-GBSA free energy calculations (Kollman et al, 2000), Mupro (Cheng et al, 2006), and SDM, a server for predicting effects of mutations on protein stability and malfunction (Worth et al, 2011). DOI:http://dx.doi.org/10.7314/APJCP.2014.15.5.2027 …”

Molecular Mechanisms of Raccoon Rabies Virus Progression in Its Natural Host

“…Structural predictions were performed on a SWISS-MODEL using automated mode for both the wildtype and mutant [38] [39]. The structural stability was assessed on SDM (a server for predicting effects of mutations on protein stability and malfunction: [40]). …”