Table 3.

Predictive power of the differences between wild type and variant proteins for different structural properties.

Property	FPR	TPR	Best MCC	Threshold	MCC90
FoldX energy evaluation
Overall stability difference	73	85	0.15	-0.45	0.14
Overall stability diff. (surface)	0	8	0.2	3.1	0.13
Overall stability diff. (buried)	21	44	0.25	2.64	0.12
Backbone clash	91	99	0.18	-1.00	-0.02
Backbone H bond	59	83	0.26	-0.025	0.06
Sidechain H bond	79	92	0.18	-0.13	-0.14
Electrostatics	6	18	0.18	0.15	0.16
Entropy main chain	6	18	0.18	0.15	0.04
Entropy side chain	64	74	0.11	-0.125	-0.05
Solvation hydrophobic	57	75	0.19	-0.15	-0.03
Solvation polar	22	36	0.15	0.20	-0.05
Torsion clash	1	3	0.07	1.00	-0.05
Van der Waals contribution	7	14	0.11	0.89	0.10
Van der Waals clash	98	100	0.10	-1.60	0.02
Entropy difference by sampling of possible side chain conformations
FoldX entropy difference	85	92	0.11	-1.85	-0.02
FoldX entropy diff. (buried)	96	100	0.14	-2.70	-0.05
FoldX entropy diff. (surface)	37	57	0.20	-0.10	0.02
Aggregation properties
Tango	1	3	0.07	39.9	0
Tango (positive, more aggr.)	14	22	0.10	16.37	0
Tango (negative, less aggr.)	69	78	0.10	-8.00	0
Waltz	0	1	0.07	748.97	0
Waltz (positive, more aggr.)	16	21	0.06	677.15	0
Waltz (negative, less aggr.)	99	100	0.07	-2412.78	0
Limbo	17	33	0.18	5.45	0

FoldX was used to evaluate both the overall stability difference between wild type and variant structure, and the constituting contributions leading to this stability difference. The entropy difference caused by the amino acid substitution was calculated using a sampling strategy to assess the possible side chain conformations allowed at the substitution site. Both stability and entropy difference 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 S2 in Additional file 1.