Using structural bioinformatics to investigate the impact of non synonymous SNPs and disease mutations: scope and limitations

Table 2 Predictive power of structural properties of the modeled variant proteins.

Property	FPR	TPR	Best MCC	Threshold	MCC90
FoldX energy evaluation
Overall stability of residue	14	33	0.22	1.61	0.19
Backbone H bond	32	72	0.40	-1.05	0.22
Sidechain H bond	99	100	0.07	-1.76	< 0
Electrostatics	86	93	0.11	-0.10	-0.01
Entropy side chain	59	80	0.22	0.32	0.05
Entropy main chain	13	27	0.18	1.96	0.10
Van der Waals contribution	25	47	0.23	-0.98	0.15
Solvation hydrophobic	10	22	0.16	-0.6	0.16
Solvation polar	42	70	0.28	1.5	0.06
Van der Waals clash	18	33	0.17	0.22	0.15
Side chain burial	51	67	0.16	0.43	-0.1
Main chain burial	59	83	0.26	0.73	0.05
Entropy by sampling of possible side chain conformations
Entropy side chain	72	84	0.15	0.93	0

The false positive rate (FPR = 1 - specificity) and the true positive rate (TPR = sensitivity) for the threshold on the specific property that gave the best Matthews correlation coefficient (MCC) are shown. MCC90 is the Matthews correlation coefficient for a specificity of 90% (i.e. 10% false positive rate). The ROC curves corresponding with the evaluation of all properties can be found in Supplementary Figure S2 in Additional file 1. FoldX was used to evaluate both the overall stability contribution of the amino acid substitution site in the modeled structure and the various factors involved in this stability. The entropy of the variant amino acid was calculated using a sampling strategy to assess the possible side chain conformations allowed at the substitution site. Both stability and entropy were calculated for all mutations and for a subset of buried mutations (side chain burial < 0.5) and surface mutations (side chain burial ≥ 0.5). Corresponding ROC curves are shown in Supplementary Figure S3 in Additional file

ISSN: 1471-2105