Rare Event Dynamics Involving Membrane Systems and CADD

Dong-Qing Wei, Ruoxu Gu, Huameng Fan, Qin Xu, Yi Xiong

State Key Lab. Of Microbial Metabolism and College of Life Science and Biotechnology, Shanghai Jiaotong University, Shanghai 200240, China


The mechanism of transmembrane ion permeation is studied using charged methyl guanidine as a model ion[1]. With a widely applied reaction coordinate, our umbrella sampling results reveal a significant finite-size effect in small simulation systems and a serious hysteresis in large systems. Therefore, it is important to re-examine the simulation techniques for studying transmembrane permeation mechanism of ions suggested in previous works. In this work, two novel collective variables are designed to acquire a continuous trajectory of the permeation process and small statistical errors through umbrella sampling. A water-bridge mechanism is discussed in detail. In this mechanism, a continuous water chain (or a chain of water molecules and lipid head groups) is formed across the membrane to conduct the transmembrane permeation of charged methyl guanidine. We obtain a continuous transition trajectory by combining the two-dimensional umbrella sampling in the local region of the saddle state and a one-dimensional sampling in the out region. Our free energy analysis shows that, with the presence of the water bridge, the energy barrier of the transmembrane permeation of ions is reduced significantly. Further studies were made for the permeation processes of some well-known ions, sodium, potassium, and chloride[2,3]. It is found permeations of sodium and potassium are assisted by important lipid bilayer deformations and massive water solvation, while chloride may not. Chloride may have two different possible pathways, in which the energetic favorable one is similar to the solubility-diffusion model. The free energy barriers for the permeation of these ions are in semiquantitative agreement with experiments. Further analyses on the distributions of oxygens and interaction energies suggests, the electrostatic interactions between ions and polar headgroups of lipids may greatly influence membrane deformation as well as the water wire, and furthermore the free energy barriers of waterwire mediated pathways. For chloride, the non-water wire pathway may be energetically favorable.

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))[4-6].

A new agonist of a membrane protein, α7nAChR was discovered with above mentioned simulation technology[7,8], 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.

Destabilization of cellular ionic homeostasis by toxic β-amyloid (Aβ) channels/barrels, which is a pathogenic mechanism for Alzheimer’s disease (AD)[9], is inhibited by wgx-50 significantly. Molecular dynamics (MD) simulations are conducted to investigate wgx-50-Aβ channels/barrels interactions, as well as the ion conductance inhibition mechanism. Ion influx from extracellular side to the central pore, which is found in apo-form simulations, is blocked by wgx-50 ligands that bind to the hydrophobic rings at the entrance of the channels/barrels. WGX-50 binding results in smaller pore diameter of the channels/barrels, however the overall morphology of them remains unaffected in accessible simulation time. WGX-50 binding site in this work consists with what we found in our previous simulations of Aβ protofibril. Our work not only investigates the ligand-Aβ channels/barrels interaction mechanism, but also provides insights into rational drug design of Alzheimer’s disease.

Key words: Transmembrane Permeation, Free Energy Calculations, M2 Channel, α7nAChR, Drug Candidate Against AD


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. Hui-Yuan Zhang, Qin Xu*, Yu-Kun Wang, Tang-Zhen Zhao, Dan Hu, Dong-Qing Wei*, “The Passive Transmembrane Permeation Mechanisms of Monovalent Ions Explored by Molecular Dynamics Simulations”. Journal of Chemical Theory and Computation 12,4959-4969(2016).

3. Cheng-Dong Li, Qin Xu, Ruo-Xu Gu*, Jing Qu, Dong-Qing Wei*, “The Dynamic Binding of Cholesterol to the Multiple Sites of C99: Revealed by Coarse-Grained and All-Atom Simulations”, Physical Chemistry Chemical Physics 01/2017;, DOI:10.1039/C6CP07873G

4. Ruo Xu Gu, Limin Angela Liu and Dong Qing Wei,(2011) J. Am. Chem. Soc. 133 (28) 10817–10825.

5. Ruo-Xu Gu, Limin Angela Liu*, Dong-Qing Wei*, “Structural and Energetic Analysis on Drug Inhibition of the Influenza A M2 Proton Channel”, Trends in Pharmacological Sciences, 34, 571(2013).

6. Ruo-Xu Gu, Limin A. Liu, Yong-Hua Wang*, Qin Xu, Dong-Qing Wei*,“Structural comparison of the wild type and drug resistant mutants of the influenza M2 proton channel by molecular dynamics simulations”,J. Phys. Chem. B., 117 (20), 6042–6051(2013).

7. 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).

8. Huai-Meng Fan, Ruo-Xu Gu, Yun-Long Pi, Yan-Jing Wang,Yonghong Zhang, Qin Xu, Dong-Qing Huang Wei, “The Destabilization of Alzheimer's Aβ42 Protofibrils with a Novel Drug Candidate WGX-50 by Molecular Dynamics Simulations”, J. Phys. Chem. B., 119 (34): 11196-202(2015).

9. Shuang Hou, Ruo-Xu Gu and Dong-Qing Wei, “Inhibition of β-Amyloid Channels with a Drug Candidate wgx-50 Revealed by Molecular Dynamics Simulations”, Journal of Chemical Information and Modeling 57(11), DOI 10.1021/acs.jcim.7b00452(2018).