Low resolution protein mapping and KB-R7943 drug-protein molecular interaction analysis of long-QT syndrome linked KCNH2 mutations

Figures & data

Table 1. Basic characteristics of KCNH2 missense variants analyzed in this study.

Gene		Genomic		cDNA	Codon
Symbol	rsID	Location	Alleles	Location	Change	Exon	Protein effect
KCNH2	rs199473524	7:150951555-55	C/T	c.2246 C > T	aCg/aTg	7/15	T613M
	rs199472971	7:150951471-71	C/T	c.2330 C > T	tCc/tTc	7/15	S641F
	rs199472975	7:150951451-51	G/A	c.2350 G > A	Ggc/Agc	7/15	G648S

Table 2. Shows pathogenic predictions scores and amino acid changes of all three CA linked KCNH2 mutaions.

				Pathogenic Predictions
S.No.	Mutation ID	Amino acid	SIFT	Polyphen-2	DUET Score (ΔΔG)
1	rs199472975	G648S	Deleterious (0)	probably_damaging (0.995)	−3.137 Kcal/mol (Destabilizing)
2	rs199472971	S641F	Deleterious (0)	probably_damaging (0.997)	−3.066 Kcal/mol (Destabilizing)
3	rs199473524	T613M	Deleterious (0)	probably_damaging (0.998)	−1.501 Kcal/mol (Destabilizing)

Figure 1. Molecular view of built KCNH2 model (a) cytosolic N-terminal PAS domain (b) voltage gated transmembrane domain (VAS) (c) cytosolic C-terminal domain.

Figure 2. Shows the superpose simulation of both wild type KCNH2 against its mutated protein models, with description of the amino acid changes and their RMSD values at the position of the all mutations.

Figure 3. KCNH2 mutations site secondary structural elements at KCNH2 Wild and mutant models.

Figure 4. Illustration of the docking simulation combining all KB-R7943 with KCNH2 with (a) wild type protein model (b) mutant Thr613Meth protein model (c) mutant Ser641Phe protein model (d) mutant Gly648Ser protein model.

Table 3. Auto dock binding energies of KB-R7943 with KCNH2 wild and mutant forms.

Complex	Cluster	Binding energy (Kcal/mol)	Amino acid interaction
Wild type KCNH2 – KB-R7943	16	−6.1	Ala558, Thr623
Mutant G648S – KB-R7943	29	−7.1	Glu575, Ser536
Mutant S641P – KB-R7943	45	−7.8	Thr613, Asn629
Mutant T613M – KB-R7943	32	−7.7	Thr523, Asp609