Influence of the SNPs on the structural stability of CBS protein: Insight from molecular dynamics simulations

doi:10.1007/s11515-014-1320-4

Front. Biol.

2014, Vol. 9

Issue (6) : 504-518 https://doi.org/10.1007/s11515-014-1320-4

RESEARCH ARTICLE

Influence of the SNPs on the structural stability of CBS protein: Insight from molecular dynamics simulations

C. GEORGE PRIYA DOSS^1,^*(

),B. RAJITH¹,R. MAGESH²,A. ASHISH KUMAR³

1. Medical Biotechnology Division, School of Biosciences and Technology, VIT University, Vellore-14, TamilNadu, India
2. Department of Biotechnology, Faculty of Biomedical Sciences, Technology & Research, Sri Ramachandra University, Chennai-600116, TamilNadu, India
3. Bioinformatics Division, School of Biosciences and Technology, VIT University, Vellore-14, TamilNadu, India

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Abstract

Cystathionine β-synthase is an essential enzyme of the trans-sulfuration pathway that condenses serine with homocysteine to form cystathionine. Missense mutations in CBS are the major cause of inherited homocystinuria, and the detailed effect of disease associated amino acid substitutions on the structure and stability of human CBS is yet unknown. Here, we apply a unique approach in combining in silico tools and molecular dynamics simulation to provide structural and functional insight into the effect of SNP on the stability and activity of mutant CBS. In addition, principal component analysis and free energy landscape were used to predict the collective motions, thermodynamic stabilities and essential subspace relevant to CBS function. The obtained results indicate that C109R, E176K and D376N mutations have the diverse effect on dynamic behavior of CBS protein. We found that highly conserved D376N mutation, which is present in the active pocket, affects the protein folding mechanism. Our strategy may provide a way in near future to understand and study effects of functional nsSNPs and their role in causing homocystinuria.

Keywords CBS in silico molecular dynamics simulation SNPs

Corresponding Author(s): C. GEORGE PRIYA DOSS

Issue Date: 13 January 2015

Cite this article:

C. GEORGE PRIYA DOSS,B. RAJITH,R. MAGESH, et al. Influence of the SNPs on the structural stability of CBS protein: Insight from molecular dynamics simulations[J]. Front. Biol., 2014, 9(6): 504-518.

URL:

https://academic.hep.com.cn/fib/EN/10.1007/s11515-014-1320-4
https://academic.hep.com.cn/fib/EN/Y2014/V9/I6/504

Variants	Amino Acid position	SIFT	Polyphen 2.0	I Mutant 3
VAR_046921	R18C	0.18	0.453	–
rs201827340	R18C	0.18	0.453	–
rs201372812	R45W	0.01	0.998	-1.27
rs148865119	P49L	0.01	0.977	-0.08
VAR_008049	P49L	0.01	0.977	-0.08
VAR_008050	R58W	0.01	0.982	??0.16
rs199507134	E62K	0.98	0.012	-1.04
VAR_021790	H65R	0	0.982	??0.05
rs17849313	A69P	0.94	0.00	??0.32
rs185581633	P70L	0.68	0	??0.6
rs192232907	K72I	0.16	0.001	??0.12
VAR_002171	P78R	0.05	0.968	-0.21
VAR_008051	G85R	0	1	-0.3
VAR_002172	P88S	0	1	-1.37
rs71322503	R91K	0.37	0.008	-1.14
rs112029370	F99Y	1	0	-0.81
VAR_021791	L101P	0	1	-0.12
rs34040148	K102Q	0.07	0.301	-1.36
VAR_002173	K102N	0	0.994	-1.61
VAR_021792	C109R	0	1	-2.32
rs121964964	A114V	0.05	0.988	-1.55
VAR_002174	A114V	0.05	0.988	-1.55
VAR_008053	G116R	0	1	??0.03
VAR_008054	R121C	0	1	-1.95
VAR_008055	R121H	0	1	-2.18
VAR_008056	R121L	0	1	-1.11
VAR_046923	R125P	0	1	-2.2
VAR_002175	R125Q	0.02	1	-2.19
VAR_008057	R125W	0	1	-1.64
VAR_008058	M126V	0	0.997	-0.11
VAR_008059	E128D	0.04	0.396	-1.11
VAR_002176	E131D	0	0.964	-0.5
rs140002610	R132C	0.01	0.998	??0.6
rs147474549	G134R	0	0.999	-0.08
rs144832032	T135M	0.23	0.057	-0.48
VAR_008060	G139R	0	1	-1.44
VAR_021793	I143M	0	1	??0.12
VAR_002177	E144K	0	1	-0.75
VAR_002178	P145L	0	1	-0.64
VAR_008061	G148R	0	1	-0.83
VAR_008062	G151R	0	1	-0.41
VAR_008064	I152M	0	0.985	??0.78
VAR_046924	L154Q	0	1	-0.82
VAR_008065	A155T	0	0.999	-2.06
VAR_046925	A155V	0	1	-0.7
rs199817801	A157T	0.12	0.106	-2.28
VAR_002179	C165Y	0.07	1	-0.63
VAR_046926	V168A	0.01	0.947	-0.75
rs121964970	V168M	0.01	1	-0.21
VAR_002180	V168M	0.01	1	-0.21
VAR_046927	M173V	0	0.651	-1.1
VAR_008066	E176K	0	1	-2.43
VAR_008067	V180A	0.25	0.014	-0.49
rs149649130	R182W	0	1	-0.02
rs138314784	R182Q	0.01	0.919	-0.55
VAR_008068	T191M	0	1	-1.72
VAR_008069	D198V	0	0.997	-0.27
VAR_066099	P200L	0	0.993	-1.31
rs201118737	K211R	0.2	0	-1.22
rs139456571	R224C	0.02	0.872	-0.79
VAR_002181	R224H	0.03	0.782	-0.72
VAR_008070	A226T	0.11	0.353	-0.94
VAR_021794	N228K	0	1	-0.55
VAR_046928	N228S	0	1	-0.66
VAR_046929	A231P	0	0.97	??0.07
VAR_008071	D234N	0.01	0.998	-0.99
VAR_002182	E239K	0	1	-0.7
rs148257986	M250I	0.01	0.667	??0.54
VAR_002183	T257M	0	1	??0.21
rs143124288	G259S	0	1	-1.16
VAR_008072	T262M	0	1	-0.31
VAR_021795	T262R	0	1	-0.51
rs121964969	R266K	0.09	0.59	-0.88
VAR_008073	R266G	0	0.995	–
VAR_021796	C275Y	0	0.998	-0.2
VAR_066100	I278S	0	0.99	-0.64
rs117019516	I278T	0	0.967	-0.12
VAR_066101	D281N	0.02	0.998	-1.9
rs147040567	I286V	0.16	0.002	??0.19
VAR_046932	A288P	0	0.98	-0.3
VAR_046933	A288T	0	0.986	-0.28
rs141502207	A288S	0.03	0.593	–
VAR_002185	P290L	0	0.997	–
rs201155833	E291D	0.3	0	-0.67
VAR_008076	E302K	0.17	0.616	-0.15
VAR_008077	G305R	0	1	??0.27
VAR_002186	G307S	0	1	-0.22
VAR_008078	V320A	0.07	0.977	-1.12
VAR_066102	D321V	0	1	-0.9
VAR_008079	A331E	0	0.711	-0.33
VAR_002187	A331V	0.01	0.845	-0.16
VAR_002188	R336C	0	1	-0.62
VAR_008080	R336H	0	1	-1.32
VAR_021797	L338P	0	1	-0.5
VAR_021798	G347S	0	0.999	-1.93
VAR_021799	S349N	0	0.986	-0.72
VAR_008081	S352N	0.01	0.566	-0.21
VAR_008082	T353M	0	0.102	-0.17
rs121964972	T353M	0	0.102	-0.17
VAR_008083	V354M	1	0.016	-0.42
VAR_021800	A355P	0.19	0.66	-0.03
rs148589243	V358M	0.09	0.412	-0.16
VAR_046934	A361T	0.01	0.482	-0.83
VAR_008084	R369C	0	1	-0.44
rs11700812	R369P	0	1	-0.09
rs11700812	R369H	0	1	-0.72
VAR_008085	C370Y	0	1	-0.54
VAR_002190	V371M	0	1	??0.06
VAR_046935	D376N	0	1	-2.07
VAR_021801	R379Q	0.01	0.847	-0.99
VAR_046936	R379W	0	1	-0.31
VAR_002191	K384E	0.01	0.996	-1.2
rs121964967	K384E	0.01	0.996	-1.2
VAR_008086	K384N	0	0.999	-1.69
VAR_008087	M391I	0.01	0.414	??0.13
rs28934892	P422L	0.11	0.9	–
rs138211175	V425M	0.01	0.983	-0.8
VAR_008088	T434N	0	0.86	-0.54
VAR_008089	I435T	0.07	0.528	-0.64
VAR_008090	R439Q	0.19	0.212	-0.25
rs28934891	D444N	0.05	0.122	-0.46
VAR_066103	A446S	0	0.336	-1.79
rs201585750	A452V	0.07	0.012	–
VAR_002193	V454E	1	0	–
VAR_021803	L456P	0.04	0.999	-0.56
rs141428279	M464T	0	0.999	-2.21
rs121964971	S466L	0.01	0.376	??0.2
VAR_008091	S466L	0.01	0.376	??0.2
rs201098477	G471R	0.21	0.752	-1.62
VAR_008092	R491C	0.08	0.002	-0.45
rs200613751	M505I	0.43	0	–
rs145228319	E514K	0.5	0.012	-1.28
rs201916339	G522R	0.02	0.027	??0.1
VAR_046937	Q526K	0.98	0	–
VAR_008093	V534D	0	0.996	-1.37
VAR_002194	L539S	0	0.996	-0.93
rs121964968	L539S	0	0.996	-0.93
rs139651937	A545S	0.65	0.001	-1.91
rs150828989	R548Q	0.7	0.007	-0.67
VAR_046938	R548Q	0.7	0.007	-0.67

Tab.1 Analysis of functional SNPs in CBS gene using SIFT, PolyPhen 2 and I Mutant 3.0 tools

Tab.2 Potential cis-acting regulatory elements affected by nsSNPs identified by expression quantitative trait loci analysis

Tab.3 Total energy of native and mutant structures before and after energy minimization.

Fig.1 (A) Time evolution of backbone RMSDs are shown as a function of time of the wild and mutant structures at 6000 ps. The symbol coding scheme is as follows: wild (black color), mutant C109R (blue color), E176K (green color) and D376N (red color). (B) RMSF of the backbone carbon alpha over the entire simulation. The ordinate is RMSF (nm), and the abscissa is atom. The symbol coding scheme is as follows: wild (black color), mutant C109R (blue color), E176K (green color) and D376N (red color). (C) Rg of the protein backbone over the entire simulation. The ordinate is Rg (nm), and the abscissa is residue. The symbol coding scheme is as follows: wild (black color), mutant C109R (Blue color), E176K (green color) and D376N (red color). (D) Solvent accessible surface of protein over the entire simulation. The ordinate is SASA (nm²), and the abscissa is atom. The symbol coding scheme is as follows: wild (black color), mutant C109R (blue color), E176K (green color) and D376N (red color). (E) Analysis of Intermolecular NH bond of native and mutant model protein at 6000ps. Average number of intermolecular hydrogen bond in native and mutant versus time. The symbol coding scheme is as follows: wild (black color), mutant C109R (blue color), E176K (green color) and D376N (red color).

Fig.2 2D projection of first two principal eigenvector and comparison of free energy landscape of native and mutant CBS protein at 300K. (A) 2D Projection of native CBS at 300K. (B) Free energy landscape of native CBS. (C) 2D Projection of mutant C109R CBS at 300K. (D) Free energy landscape of Mutant CBS. (E) 2D Projection of mutant E176K CBS at 300K. (F) 2D Free energy landscape of mutant E176K CBS. (G) 2D Projection of mutant D376N CBS at 300K. (H) Free energy landscape of mutant D376N CBS.

Fig.3 The conservation pattern of amino acid sequence in CBS. The location of amino acid residues in CBS based on the evolutionary conservation pattern. Red color box indicate the position of native amino acid position which are predicted to be most functionally significant by various in silico tools. Color intensity increases with the degree of conservation.

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