Molecular Dynamics Simulation on the Conformational Changes of CYP2E1 Enzyme Under Different Concentrations of Ethyl Alcohol

doi:10.7503/cjcu20150628

Abstract

Abstract:

Cytochrome P450(CYP) 2E1 is a dual function monoxygenase with a crucial role in the metabolism of 6% of drugs on the market at present. The enzyme is of tremendous interest for its association with alcohol consumption, diabetes, obesity and fasting. The enzyme’s conformational changes at different ethanol concentrations have not been rationalized at the atomic level. In this regard, we have investigated the effects of different ethanol concentrations on the structural and energetic characteristics upon the complex of arachidonic acid and CYP2E1(AA-CYP2E1). The molecular dynamics(MD) simulation combined with binding free energy calculations was carried out on AA-CYP2E1 complex at different ethanol concentrations. Based on the MD simulation results, two residues, His109 and Lys243, are responsible for the binding of AA molecule. The binding ability of AA molecue is decreased at high concentrations of ethanol. This is due to the loss of certain hydrogen bond interaction. The high concentration of ethanol can also affect the surface structure of AA-CYP2E1. Our work provides detailed atomistic insights into the structure-function relationships of CYP2E1 at different ethanol concentrations under dynamics conditions. This work also provides particular explanations on how different ethanol concentrations affect the surface structure of CYP2E1. Furthermore, the mutational effects on the activity of CYP2E1 obtained in the present study are beneficial to both experiment and computation of CYPs and may allow researchers to achieve desirable changes in enzymatic activities.

Key words: Cytochrome P450(CYP) 2E1 enzyme, Molecular dynamics(MD) simulation, Binding free energy calculation

CLC Number:

O641

TrendMD:

WANG Yan, ZHENG Qingchuan. Molecular Dynamics Simulation on the Conformational Changes of CYP2E1 Enzyme Under Different Concentrations of Ethyl Alcohol[J]. Chem. J. Chinese Universities, 2015, 36(11): 2226.

Figures/Tables 9

Fig.1 Calculated root-mean-square deviations(RMSD) of backbone atoms referenced to corresponding starting structure

Fig.2 Root-mean-square fluctuations(RMSF) of noeoh, 0.1eoh and 4.0eoh systems Noeoh system is represented by black lines, 0.1eoh system red lines and 4.0eoh system blue lines. The results from DSSP are shown in the top panel of this Figure. Helices are indicated in green(and labeled at the top of Figure), β-sheets in yellow and turns in purple. A, B etc. stand for the well-known helix of the CYPs family.

Fig.3 Percentage of occupancy of hydrogen bonds in different systems All these hydrogen bonds are monitored during the whole simulation time of each system.

Table 1 Properties of hydrogen bonds between AA and its adjacent residues, including occupancy, distance and angle

System	H-Bond	Occupancy(%)	Distance/nm	Angle/(°)
Noeoh	ACD@O2-H109@HE2	31.5	0.282	24.24
	ACD@O1-H109@HE2	17.4	0.289	28.27
	ACD@O2-K243@HZ1	15.2	0.287	26.96
	ACD@O2-K243@HZ3	14.6	0.285	25.47
	ACD@O2-K243@HZ2	12.5	0.288	28.99
	ACD@O1-K243@HZ1	11.3	0.296	33.47
	ACD@O1-K243@HZ2	9.7	0.292	33.05
	ACD@O1-K243@HZ3	9.0	0.297	37.29
0.1eoh	ACD@O1-K243@HZ1	29.3	0.278	20.20
	ACD@O1-K243@HZ2	24.3	0.277	20.98
	ACD@O2-H109@HE2	20.8	0.278	36.56
	ACD@O1-K243@HZ3	19.3	0.280	21.44
	ACD@O2-K243@HZ1	13.8	0.284	21.93
	ACD@O2-K243@HZ3	11.2	0.283	22.37
	ACD@O2-K243@HZ2	7.0	0.292	25.33
4.0eoh	ACD@O1-H109@HE2	76.6	0.285	26.60
	ACD@O2-H109@HE2	74.7	0.290	29.89

Fig.4 Electrostatic potential surface of AA molecule

Fig.5 Alignment of three representative structures for noeoh, 0.1eoh and 4.0eoh systems All the structures are in ribbon style. Noeoh is colored in light gray, 0.1eoh in deep sky cyan and 4.0eoh in orchid. A close view for AA molecule and heme are presented on the right.

Table 2 Populations of representative structures and their RMSD values compared to noeoh representative structure

Structure	Population(%)	RMSD to noeoh structure/nm
C4	41.2	0.116
C3	38.5	0.132

Fig.6 Porcupine plots in stereo showing noeoh(A), 0.1eoh(B) and 4.0eoh(C) with cones signifying the first eigenvectors movements Noeoh system is colored in cyan, N219D in purple and S366C in orange.

Table 3 Binding free energies and their components for noeoh, 0.1eoh and 4.0eoh

System	ΔE_ele/(kJ·mol^-1)	ΔE_vdw/(kJ·mol^-1)	ΔG_GB/(kJ·mol^-1)	ΔG_SA/(kJ·mol^-1)	-TΔS/(kJ·mol^-1)	Δ $G bind *$ /(kJ·mol^-1)
Noeoh	-633.80	-162.00	675.70	-22.27	75.72	-66.64
0.1eoh	-1040.14	-156.35	995.97	-29.22	180.25	-49.44
4.0eoh	-1047.84	-165.18	1008.24	-18.63	209.93	-13.48

Table 3 Binding free energies and their components for noeoh, 0.1eoh and 4.0eoh

System	ΔE_ele/(kJ·mol^-1)	ΔE_vdw/(kJ·mol^-1)	ΔG_GB/(kJ·mol^-1)	ΔG_SA/(kJ·mol^-1)	-TΔS/(kJ·mol^-1)	Δ $G bind *$ /(kJ·mol^-1)
Noeoh	-633.80	-162.00	675.70	-22.27	75.72	-66.64
0.1eoh	-1040.14	-156.35	995.97	-29.22	180.25	-49.44
4.0eoh	-1047.84	-165.18	1008.24	-18.63	209.93	-13.48

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