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Free Energy Calculations of Membrane Systems and CADD

Dongqing WEI
Shanghai Jiaotong University

Techniques of rare event dynamics were improved[1] and implemented along with biochemical simulation packages. Charged methyl guanidine is used as a model ion to study the transmembrane permeation of ions. With a widely applied reaction coordinate, our umbrella sampling discovers a dilemma in obtaining the transition trajectory and the potential of mean force — significant finite-size effect in small systems and serious hysteresis in large systems. This suggests the importance of
re-examining the validity of the transition trajectory and the potential of mean force obtained in previous works. In this work, a novel reaction coordinate is designed to acquire a continuous trajectory of the permeation process in a large simulation system. This continuous trajectory demonstrates the presence of a water pore at the saddle state which is not clearly observed in previous works. With the presence of the water pore, the energy barrier is shown to be significantly decreased.
Applications were made to study biological systems with relevance to drug design and drug metabolism. The rare event dynamics simulations were performed to understand the kinetic and thermodynamic free energy information on the drug binding sites in the M2 proton channel. Our results give a theoretical framework to interpret and reconcile existing and often conflicting results regarding these two binding sites, thus helping to expand our understanding of M2 drug binding, and may help guide the design and screening of novel drugs to combat the virus (JACS, 133, 10817 (2011))[2].
A new agonist of a membrane protein, α7nAChR was discovered with above mentioned simulation technology[3-7], i.e., wgx50, which was tested in vitro experiments that it could combine with α7nAChR on nerve cells, induce depolymerization of Aβ, inhibit Aβ-induced neurocyte apoptosis, and suppress the release of TNF-αand IL-1β from microglia. In vivo experiments showed that it could improve the cognition ability in APP-Transgenic Mice. These results suggest that wgx50 is a promising drug candidate for AD treatment.

1.    Yukun Wang, Dan Hu and Dong-Qing Wei, “Transmembrane Permeation Mechanism of Charged Methyl Guanidine”, J. Chem. Theory Comput., 10 (4), 1717–1726(2014).
2.    Ruo Xu Gu, Limin Angela Liu and Dong Qing Wei,(2011) J. Am. Chem. Soc. 133 (28) 10817–10825.
3.    H. R. Arias, Ruo-Xu Gu, Dominik Feuerbach, Bao-Bao Guo, Yong Ye, and D.Q. Wei*, “Novel Positive Allosteric Modulators of the Human α7 Nicotinic  Acetylcholine Receptor”, Biochemistry,  50, 5263–5278(2011).
4.    Peng Lian, Dong-Qing Wei*, Jing-Fang Wang*, Kuo-Chen Chou,  “An Allosteric Mechanism Inferred from Molecular Dynamics Simulations on Phospholamban Pentamer in Lipid Membranes”, PLoS ONE ,  6,  e18587(2011).
5.    Hugo R. Arias*, Ruo-Xu Gu,  Dominik Feuerbach,and Dong-Qing Wei, “Different interaction between the agonist JN403 and the competitive antagonist methyllycaconitine with the human alpha7 nicotinic acetylcholine receptor”, Biochemistry, 49, 4169-4180(2010).
6.    Maoping Tang, Zhaoxia Wang, Ying Zhou, Wangjie Xu, Shengtian Li,Lianyun Wang, Dong-Qing Wei*, Zhongdong Qiao*, “A novel drug candidate for Alzheimer disease treatment - gx-50 derived from Zanthoxylum Bungeanum”, J. Alzheimer’s Disease, 34, 203–213 (2013).