Molecular Dynamics Simulation Study on the Binding Modes of Angiotensin-converting Enzyme with Inhibitory Peptides†

doi:10.7503/cjcu20170007

Abstract

Abstract:

Binding modes of C-domain of Angiotensin-converting enzyme(ACE) and two peptides RIGLF and AHEPVK which had competitive inhibited potency against ACE, C-domain-RIGLF and C-domain-AHEPVK were investigated with molecular docking, molecular dynamics simulation, and binding free energy, calculation. The calculation results indicate that vital binding residues in C-domain-RIGLF are His353, Asp377, Asp453, Phe457, His513, Tyr523 and Phe527, while key residues in C-domain-AHEPVK are Gln281, His353, Ser355, Glu384, Lys511, His513 and Tyr523. The binding ability between C-domain-RIGLF and C-domain-AHEPVK were compared via MM-PBSA calculation. The calculated results indicate that AHEPVK binds C-domain more easily than RIGLF. The result is consistent with experimental data. The results have academic guidance meaning for exploring the mechanism of how foodborne peptide inhibitors bind to ACE and this work provides the clues for novel medicines design which are mainly aimed at ACE.

Key words: Angiotensin-converting enzyme, Inhibitory peptide, Molecular docking, Molecular dynamics simulation, Free energy calculation

CLC Number:

O641

TrendMD:

WANG Song, GUAN Shanshan, WAN Yongfeng, SHAN Yaming, ZHANG Hao. Molecular Dynamics Simulation Study on the Binding Modes of Angiotensin-converting Enzyme with Inhibitory Peptides^†[J]. Chem. J. Chinese Universities, 2017, 38(7): 1216.

Figures/Tables 6

Table 1 Simulation information of two complex systems

Simulation system	Simulation time/ns	Number of solvent molecules	Number of counter ions	Number of Cl^-/Zn²⁺
C-domain-RIGLF	100	27191	12 Na⁺	2/1
C-domain-AHEPVK	100	27187	13 Na⁺	2/1

Fig.1 RMSD of backbone Cα atoms of C-domain-RIGLF(a) and N-domain-AHEPVK(b) with respect to their initial structures as function of time during 100 ns

Fig.2 Predicted binding modes and key residues of two systems C-domain-RIGLF(A) and C-domain-AHEPVK(B)

Fig.3 Decomposition of the binding energy on per residue basis on two systems C-domain-RIGLF(A) and C-domain-AHEPVK(B) : the total binding energy contribution form per

Fig.4 Comparative B-factor between C-domain-RIGLF(A) and C-domain-AHEPVK(B)

Table 2 Calculated energy components, binding free energy of C-domain-RIGLF and C-domain-AHEPVK*

Energy component	C-domain-RIGLF	C-domain-AHEPVK
ΔE_vdw/(kJ·mol^-1)	-240.91	-252.80
ΔE_ele/(kJ·mol^-1)	-2371.28	-1906.96
ΔE_MM/(kJ·mol^-1)	-2612.19	-2159.72
ΔG_ele,sol/(kJ·mol^-1)	-41.49	-41.11
ΔG_nonpolar,sol/(kJ·mol^-1)	2419.64	1944.06
ΔG_sol/(kJ·mol^-1)	2378.14	1902.94
(Δ $G ele, sol$ +ΔE_ele)/(kJ·mol^-1)	-2412.77	-1948.08
(Δ $G nonpolar, so l$ +ΔE_vdw)/(kJ·mol^-1)	2178.73	1691.26
ΔG_total/(kJ·mol^-1)	-234.04	-256.82

Table 2 Calculated energy components, binding free energy of C-domain-RIGLF and C-domain-AHEPVK*

Energy component	C-domain-RIGLF	C-domain-AHEPVK
ΔE_vdw/(kJ·mol^-1)	-240.91	-252.80
ΔE_ele/(kJ·mol^-1)	-2371.28	-1906.96
ΔE_MM/(kJ·mol^-1)	-2612.19	-2159.72
ΔG_ele,sol/(kJ·mol^-1)	-41.49	-41.11
ΔG_nonpolar,sol/(kJ·mol^-1)	2419.64	1944.06
ΔG_sol/(kJ·mol^-1)	2378.14	1902.94
(Δ $G ele, sol$ +ΔE_ele)/(kJ·mol^-1)	-2412.77	-1948.08
(Δ $G nonpolar, so l$ +ΔE_vdw)/(kJ·mol^-1)	2178.73	1691.26
ΔG_total/(kJ·mol^-1)	-234.04	-256.82

References 32

[1]	Tanzadehpanah H., Asoodeh A., Saberi M. R., Chamani J., Innov. Food Sci. Emerg., 2013, 18, 212—219
[2]	Pihlanto A., Virtanen T., Korhonen H., Int. Dairy. J., 2010, 20(1), 3—10
[3]	Masuyer G., Akif M., Czarny B., Beau F., Schwager S. L., Sturrock E. D., Isaac R. E., Dive V., Acharya K. R., FEBS J., 2014, 281(3), 943—956
[4]	Hu J., Igarashi A., Kamata M., Nakagawa H., J. Biol. Chem., 2001, 276(51), 47863—47868
[5]	Geng X. R., Tian G. T., Zhang W. W., Zhao Y. C., Zhao L. Y., Wang H. X., Ng T. B., Scientific Reports,2016, 6, 24130
[6]	Iwaniak A., Minkiewicz P., Darewicz M., Compr. Rev. Food Sci. F., 2014, 13(2), 114—134
[7]	Conrad N., Schwager S. L. U., Carmona A. K., Sturrock E. D., Biochemical and Biophysical Research Communications,2016, 481, 111—116
[8]	Feng S. M., Limwachiranon J., Luo Z. S., Shi X. D., Ru Q. M., International Journal of Food Science and Technology,2016, 51, 1610—1617
[9]	Orona-Tamayo D., Valverde M. E., Nieto-Rendon B., Paredes-López O., LWT-Food Science and Technology,2015, 64(1), 236—242
[10]	Forghani B., Zarei M., Ebrahimpour A., Philip R., Bakar J., Hamid A. A., Saari N., Journal of Functional Foods,2016, 20, 276—290
[11]	Norris R., O'Keeffe M. B., Poyarkov A., FitzGerald R. J., Food Chemistry,2015, 188, 210—217
[12]	Gangopadhyay N., Wynne K., O'Connor P., Gallagher E., Brunton N. P., Rai D. K., Hayes M., Food Chemistry,2016, 203, 367—374
[13]	Lau C. C., Abdullah N., Shuib A. S., Aminudin N., Food Chem., 2014, 148, 396—401
[14]	Morris G. M., Huey R., Lindstrom W., Sanner M. F., Belew R. K., Goodsell D. S., Olson A. J., J. Comput. Chem., 2009, 30(16), 2785—2791
[15]	Qian M.D., Shan Y. M., Guan S. S., Zhang H., Wang S., Han W. W., Journal of Chemical Information and Modeling, 2016, 56,2024—2034
[16]	Hou X., Du J., Zhang J., Du L., Fang H., Li M., Journal of Chemical Information and Modeling,2013, 53(1), 188—200
[17]	Masuyer G., Schwager S. L., Sturrock E. D., Isaac R. E., Acharya K. R., Scientific Reports,2012, 2, 717
[18]	Guan S. S., Han W. W., Zhang H., Wang S., Shan Y. M., Journal of Biomolecular Structure and Dynamics,2016, 34(1), 15—28
[19]	Discovery Studio 2.5, Accelrys Inc.: San Diego, CA., 2009
[20]	Wang X., Wu S., Xu D., Xie D., Guo H., Journal of Chemical Information and Modeling,2011, 51(5), 1074—1082
[21]	Hess B., Kutzner C., van Der Spoel D., Lindahl E., J. Chem. Theory Comput., 2008, 4(3), 435—447
[22]	Hornak V., Abel R., Okur A., Strockbine B., Roitberg A., Simmerling C.,Proteins,2006, 65(3), 712—725
[23]	Hess B., van der Vegt N. F. A.,J. Phys. Chem.B,2006, 110(35), 17616—17626
[24]	Berendsen H. J. C., Postma J. P. M., van Gunsteren W. F., DiNola A., Haak J. R., J. Chem. Phys., 1984, 81(8), 3684—3690
[25]	Darden T., York D., Pedersen L., J. Chem. Phys., 1993, 98(12), 10089—10092
[26]	Chen X. G., Zhao X. J., Wang S., Wang L. P., Li W., Sun C. C., Acta Chim. Sinica,2013, 71(02), 199—204
	(陈晓光, 赵晓杰, 王嵩, 王丽萍, 李惟, 孙家锺.化学学报, 2013, 71(02), 199—204)
[27]	Wang S., Zhao X., Zheng Q. C., Huang X. R., Sun C. C., Chem. J. Chinese Universities,2009, 30(8), 1641—1644
	(王嵩, 赵熹, 郑清川, 黄旭日, 孙家锺.高等学校化学学报, 2009, 30(8), 1641—1644)
[28]	Case D. A., Cheatham Ⅲ T. E., Darden T., Gohlke H., Luo R., Merz K. M. Jr., Onufriev A., Simmerling C., Wang B., Woods R. J., J. Comput. Chem., 2005, 26(16), 1668—1688
[29]	Case D.A., Darden T., Cheatham Ⅲ T. E., Simmerling C., Wang J. M., Duke R. E., Luo R., Crowley M., Walker R., Zhang W., Merz K. M. Jr., Wang B., Hayik S., Roitberg A., Seabra G., Kolossváry I., Wong K. F., Paesani F., Vanicek J., Wu X. W., Brozell S. R., Steinbrecher T., Gohlke H., Yang L. J., Tan C. H., Mongan J., Hornak V., Cui G. L., Mathews D. H., Seetin M. G., Sagui C., Babin V., Kollman P. A., AMBER 10, University of California,San Francisco, 2008
[30]	Pearlman D. A., Case D. A., Caldwell J. W., Ross W. S., Cheatham Ⅲ T. E., DeBol S., Ferguson D., Seibel G., Kollman P., Comp. Phys. Commun., 1995, 91, 1—41
[31]	Weik M., Ravelli R. B. G., Kryger G., McSweeney S., Raves M. L., Harel M., Gros P., Silman I., Kroon J., Sussman J. L., P. Natl. Acad. Sci. USA,2000, 97(2), 623—628
[32]	Obradovic Z., Peng K., Vucetic S., Radivojac P., Dunker A. K., Proteins,2005, 61(S7), 176—182