Song Group

We aim at revealing the function mechanisms of membrane proteins by using multi-scale computer simulations, in collaboration with experimental studies. Our main interests currently involve the permeation mechanism of ion channels, signaling through membrane-associated proteins, and interaction between antimicrobial peptides and lipid bilayers. We also use machine learning-based methods for the structural and functional studies of membrane proteins.

Our ultimate goal is to contribute to membrane protein- or membrane-targeted drug design and optimization, and thereby to improve people’s health at large.

You can find more information about us here.

Selected Publications

AltConf
Exploring the Alternative Conformation of a Known Protein Structure Based on Contact Map Prediction

Li, Jiaxuan; Wang, Lei; Zhu, Zefeng; and Song, Chen

Journal of Chemical Information and Modeling Dec 2023

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The rapid development of deep learning-based methods has considerably advanced the field of protein structure prediction. The accuracy of predicting the 3D structures of simple proteins is comparable to that of experimentally determined structures, providing broad possibilities for structure-based biological studies. Another critical question is whether and how multistate structures can be predicted from a given protein sequence. In this study, analysis of tens of two-state proteins demonstrated that deep learning-based contact map predictions contain structural information on both states, which suggests that it is probably appropriate to change the target of deep learning-based protein structure prediction from one specific structure to multiple likely structures. Furthermore, by combining deep learning- and physics-based computational methods, we developed a protocol for exploring alternative conformations from a known structure of a given protein, by which we successfully approached the holo-state conformations of multiple representative proteins from their apo-state structures.
@article{li2023, title = {Exploring the {{Alternative Conformation}} of a {{Known Protein Structure Based}} on {{Contact Map Prediction}}}, author = {Li, Jiaxuan and Wang, Lei and Zhu, Zefeng and Song, Chen}, year = {2023}, month = dec, journal = {Journal of Chemical Information and Modeling}, doi = {10.1021/acs.jcim.3c01381}, url = {https://doi.org/10.1021/acs.jcim.3c01381}, urldate = {2023-12-22}, volume = {n/a}, number = {n/a}, pages = {1-15}, bibtex_show = {true}, selected = {true}, abbr = {AltConf} }
Cav1.2
Structural basis for human Cav1.2 inhibition by multiple drugs and the neurotoxin calciseptine

Gao, Shuai; Yao, Xia; Chen, Jiaofeng; Huang, Gaoxingyu; Fan, Xiao; Xue, Lingfeng; Li, Zhangqiang; Wu, Tong; Zheng, Yupeng; Huang, Jian; Jin, Xueqin; Wang, Yan; Wang, Zhifei; Yu, Yong; Liu, Lei; Pan, Xiaojing; Song, Chen; and Yan, Nieng

Cell Nov 2023

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Cav1.2 channels play crucial roles in various neuronal and physiological processes. Here, we present cryo-EM structures of human Cav1.2, both in its apo form and in complex with several drugs, as well as the peptide neurotoxin calciseptine. Most structures, apo or bound to calciseptine, amlodipine, or a combination of amiodarone and sofosbuvir, exhibit a consistent inactivated conformation with a sealed gate, three up voltage-sensing domains (VSDs), and a down VSDII. Calciseptine sits on the shoulder of the pore domain, away from the permeation path. In contrast, when pinaverium bromide, an antispasmodic drug, is inserted into a cavity reminiscent of the IFM-binding site in Nav channels, a series of structural changes occur, including upward movement of VSDII coupled with dilation of the selectivity filter and its surrounding segments in repeat III. Meanwhile, S4-5III merges with S5III to become a single helix, resulting in a widened but still non-conductive intracellular gate.
@article{gao_structural_2023, title = {Structural basis for human {Cav1}.2 inhibition by multiple drugs and the neurotoxin calciseptine}, volume = {186}, url = {https://www.sciencedirect.com/science/article/pii/S0092867423011066}, doi = {10.1016/j.cell.2023.10.007}, number = {24}, journal = {Cell}, author = {Gao, Shuai and Yao, Xia and Chen, Jiaofeng and Huang, Gaoxingyu and Fan, Xiao and Xue, Lingfeng and Li, Zhangqiang and Wu, Tong and Zheng, Yupeng and Huang, Jian and Jin, Xueqin and Wang, Yan and Wang, Zhifei and Yu, Yong and Liu, Lei and Pan, Xiaojing and Song, Chen and Yan, Nieng}, month = nov, year = {2023}, keywords = {voltage-gated calcium channels, amiodarone, amlodipine, Ca1.2, calciseptine, channel inactivation, L-type calcium channels, LTCC, pinaverium bromide, sofosbuvir}, pages = {5363--5374}, bibtex_show = {true}, selected = {true}, abbr = {Cav1.2} }
ProtRAP
ProtRAP: Predicting Lipid Accessibility Together with Solvent Accessibility of Proteins in One Run

Kang, Kai; Wang, Lei; and Song, Chen

Journal of Chemical Information and Modeling Jan 2023

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Solvent accessibility has been extensively used to characterize and predict the chemical properties of the surface residues of soluble proteins. However, there is not yet a widely accepted quantity of the same dimension for the study of lipid-accessible residues of membrane proteins. In this study, we propose that lipid accessibility, defined in a similar way to solvent accessibility, can be used to characterize the lipid-accessible residues of membrane proteins. Moreover, we developed a deep learning-based method, ProtRAP (Protein Relative Accessibility Predictor), to predict the relative lipid accessibility and relative solvent accessibility of residues from a given protein sequence, which can infer which residues are likely accessible to lipids, accessible to solvent, or buried in the protein interior in one run.
@article{kang2023a, title = {{{ProtRAP}}: {{Predicting Lipid Accessibility Together}} with {{Solvent Accessibility}} of {{Proteins}} in {{One Run}}}, shorttitle = {{{ProtRAP}}}, abbr = {{ProtRAP}}, url = {https://doi.org/10.1021/acs.jcim.2c01235}, bibtex_show = {true}, selected = {true}, author = {Kang, Kai and Wang, Lei and Song, Chen}, year = {2023}, month = jan, journal = {Journal of Chemical Information and Modeling}, publisher = {{American Chemical Society}}, issn = {1549-9596}, doi = {10.1021/acs.jcim.2c01235} }
MCP
Membrane contact probability: an essential and predictive character for the structural and functional studies of membrane proteins

Wang, Lei; Zhang, Jiangguo; Wang, Dali; and Song, Chen

PLoS Computational Biology Jan 2022

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One of the unique traits of membrane proteins is that a significant fraction of their hydrophobic amino acids is exposed to the hydrophobic core of lipid bilayers rather than being embedded in the protein interior, which is often not explicitly considered in the protein structure and function predictions. Here, we propose a characteristic and predictive quantity, the membrane contact probability (MCP), to describe the likelihood of the amino acids of a given sequence being in direct contact with the acyl chains of lipid molecules. We show that MCP is complementary to solvent accessibility in characterizing the outer surface of membrane proteins, and it can be predicted for any given sequence with a machine learning-based method by utilizing a training dataset extracted from MemProtMD, a database generated from molecular dynamics simulations for the membrane proteins with a known structure. As the first of many potential applications, we demonstrate that MCP can be used to systematically improve the prediction precision of the protein contact maps and structures.Competing Interest StatementThe authors have declared no competing interest.
@article{wang_membrane_2022, title = {Membrane contact probability: an essential and predictive character for the structural and functional studies of membrane proteins}, doi = {10.1371/journal.pcbi.1009972}, url = {https://doi.org/10.1371/journal.pcbi.1009972}, journal = {PLoS Computational Biology}, volume = {18}, pages = {e1009972}, author = {Wang, Lei and Zhang, Jiangguo and Wang, Dali and Song, Chen}, year = {2022}, bibtex_show = {true}, abbr = {MCP}, selected = true }
NOMPC
The push-to-open mechanism of the tethered mechanosensitive ion channel NompC

Wang, Yang; Guo, Yifeng; Li, Guanluan; Liu, Chunhong; Wang, Lei; Zhang, Aihua; Yan, Zhiqiang; and Song, Chen

eLife Jan 2021

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NompC is a mechanosensitive ion channel responsible for the sensation of touch and balance in Drosophila melanogaster. Based on a resolved cryo-EM structure, we performed all-atom molecular dynamics simulations and electrophysiological experiments to study the atomistic details of NompC gating. Our results showed that NompC could be opened by compression of the intracellular ankyrin repeat domain but not by a stretch, and a number of hydrogen bonds along the force convey pathway are important for the mechanosensitivity. Under intracellular compression, the bundled ankyrin repeat region acts like a spring with a spring constant of ~13 pN nm−1 by transferring forces at a rate of ~1.8 nm ps−1. The linker helix region acts as a bridge between the ankyrin repeats and the transient receptor potential (TRP) domain, which passes on the pushing force to the TRP domain to undergo a clockwise rotation, resulting in the opening of the channel. This could be the universal gating mechanism of similar tethered mechanosensitive TRP channels, which enable cells to feel compression and shrinkage.
@article{wang_push2open_2021, bibtex_show = {true}, title = {The push-to-open mechanism of the tethered mechanosensitive ion channel {NompC}}, volume = {10}, issn = {2050-084X}, url = {https://doi.org/10.7554/eLife.58388}, doi = {10.7554/eLife.58388}, urldate = {2021-06-09}, journal = {eLife}, author = {Wang, Yang and Guo, Yifeng and Li, Guanluan and Liu, Chunhong and Wang, Lei and Zhang, Aihua and Yan, Zhiqiang and Song, Chen}, editor = {Delemotte, Lucie and Aldrich, Richard W and Martinac, Boris and Gaudet, Rachelle}, year = {2021}, note = {Publisher: eLife Sciences Publications, Ltd}, keywords = {electrophysiology, gating, mechanosensitive ion channel, molecular dynamics, NompC}, pages = {e58388}, abbr = {NOMPC}, selected = {true} }

Ca²⁺

The Ca²⁺ permeation mechanism of the ryanodine receptor revealed by a multi-site ion model

Zhang, Aihua; Yu, Hua; Liu, Chunhong; and Song, Chen

Nature Communications Jan 2020

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Although the permeation mechanisms for K+ and Na+ channels have been extensively studied, the ion permeation mechanism through Ca2+ channels was largely unknown. Here the authors develop a multisite Ca2+ model that can be used in the framework of classical MD simulations to study Ca2+ in a quantitative manner, and use it to investigate the ion permeation mechanism of the ryanodine receptor 1.

@article{zhang_ca2_2020,
  bibtex_show = {true},
  title = {The Ca<sup>2+</sup> permeation mechanism of the ryanodine receptor revealed by a multi-site ion model},
  volume = {11},
  copyright = {2020 The Author(s)},
  issn = {2041-1723},
  url = {https://www.nature.com/articles/s41467-020-14573-w},
  doi = {10.1038/s41467-020-14573-w},
  language = {en},
  urldate = {2020-02-27},
  journal = {Nature Communications},
  author = {Zhang, Aihua and Yu, Hua and Liu, Chunhong and Song, Chen},
  year = {2020},
  pages = {C922},
  abbr = {Ca<sup>2+</sup>},
  selected = {true}
}

OSCA

Structure of the mechanosensitive OSCA channels

Zhang, Mingfeng; Wang, Dali; Kang, Yunlu; Wu, Jing-Xiang; Yao, Fuqiang; Pan, Chengfang; Yan, Zhiqiang; Song, Chen; and Chen, Lei

Nature Structural & Molecular Biology Jan 2018

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@article{zhang_structure_2018,
  bibtex_show = {true},
  title = {Structure of the mechanosensitive {OSCA} channels},
  volume = {25},
  copyright = {2018 The Author(s), under exclusive licence to Springer Nature America, Inc.},
  issn = {1545-9985},
  url = {https://www.nature.com/articles/s41594-018-0117-6},
  doi = {10.1038/s41594-018-0117-6},
  language = {en},
  number = {9},
  urldate = {2018-09-07},
  journal = {Nature Structural \& Molecular Biology},
  author = {Zhang, Mingfeng and Wang, Dali and Kang, Yunlu and Wu, Jing-Xiang and Yao, Fuqiang and Pan, Chengfang and Yan, Zhiqiang and Song, Chen and Chen, Lei},
  year = {2018},
  pages = {850--858},
  abbr = {OSCA},
  selected = {true}
}

KKK
Ion permeation in K⁺ channels occurs by direct Coulomb knock-on

Köpfer, David A.; Song, Chen; Gruene, Tim; Sheldrick, George M.; Zachariae, Ulrich; and Groot, Bert L.

Science Jan 2014

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Potassium channels selectively conduct K+ ions across cellular membranes with extraordinary efficiency. Their selectivity filter exhibits four binding sites with approximately equal electron density in crystal structures with high K+ concentrations, previously thought to reflect a superposition of alternating ion- and water-occupied states. Consequently, cotranslocation of ions with water has become a widely accepted ion conduction mechanism for potassium channels. By analyzing more than 1300 permeation events from molecular dynamics simulations at physiological voltages, we observed instead that permeation occurs via ion-ion contacts between neighboring K+ ions. Coulomb repulsion between adjacent ions is found to be the key to high-efficiency K+ conduction. Crystallographic data are consistent with directly neighboring K+ ions in the selectivity filter, and our model offers an intuitive explanation for the high throughput rates of K+ channels. Simulation shows that ions crossing a potassium channel are in direct contact with one another and repel each other through. [Also see Perspective by Hummer] Potassium channels play a key role in regulating a cell’s membrane potential, which in turn affects diverse processes. The channels contain four potassium binding sites that are thought to be alternately occupied by potassium and water. Starting from high-resolution crystal structures, Köpfer et al. simulated over a thousand potassium ions crossing the channel (see the Perspective by Hummer). They found that ions are in direct contact rather than being separated by water as previously assumed. It seems that repulsion between the ions is the key to their efficient movement through the channel. Science, this issue p. 352; see also p. 303
@article{Kopfer2014, author = {Köpfer, David A. and Song, Chen and Gruene, Tim and Sheldrick, George M. and Zachariae, Ulrich and de Groot, Bert L.}, title = {Ion permeation in K<sup>+</sup> channels occurs by direct Coulomb knock-on}, journal = {Science}, url = {http://www.sciencemag.org/cgi/doi/10.1126/science.1254840}, bibtex_show = {true}, selected = true, abbr = {KKK}, volume = {346}, number = {6207}, pages = {352-355}, year = {2014}, doi = {10.1126/science.1254840}, eprint = {https://www.science.org/doi/pdf/10.1126/science.1254840} }
DCD
Crystal structure and functional mechanism of a human antimicrobial membrane channel

Song, Chen; Weichbrodt, Conrad; Salnikov, Evgeniy S.; Dynowski, Marek; Forsberg, Björn O.; Bechinger, Burkhard; Steinem, Claudia; Groot, Bert L.; Zachariae, Ulrich; and Zeth, Kornelius

Proc. Natl. Acad. Sci. U.S.A. Jan 2013

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Multicellular organisms fight bacterial and fungal infections by producing peptide-derived broad-spectrum antibiotics. These host-defense peptides compromise the integrity of microbial cell membranes and thus evade pathways by which bacteria develop rapid antibiotic resistance. Although more than 1,700 host-defense peptides have been identified, the structural and mechanistic basis of their action remains speculative. This impedes the desired rational development of these agents into next-generation antibiotics. We present the X-ray crystal structure as well as solid-state NMR spectroscopy, electrophysiology, and MD simulations of human dermcidin in membranes that reveal the antibiotic mechanism of this major human antimicrobial, found to suppress Staphylococcus aureus growth on the epidermal surface. Dermcidin forms an architecture of high-conductance transmembrane channels, composed of zinc-connected trimers of antiparallel helix pairs. Molecular dynamics simulations elucidate the unusual membrane permeation pathway for ions and show adjustment of the pore to various membranes. Our study unravels the comprehensive mechanism for the membrane-disruptive action of this mammalian host-defense peptide at atomistic level. The results may form a foundation for the structure-based design of peptide antibiotics.
@article{song2013, author = {Song, Chen and Weichbrodt, Conrad and Salnikov, Evgeniy S. and Dynowski, Marek and Forsberg, Björn O. and Bechinger, Burkhard and Steinem, Claudia and de Groot, Bert L. and Zachariae, Ulrich and Zeth, Kornelius}, title = {Crystal structure and functional mechanism of a human antimicrobial membrane channel}, journal = {Proc. Natl. Acad. Sci. U.S.A.}, volume = {110}, number = {12}, pages = {4586-4591}, year = {2013}, doi = {10.1073/pnas.1214739110}, url = {https://www.pnas.org/doi/abs/10.1073/pnas.1214739110}, bibtex_show = {true}, selected = true, abbr = {DCD} }