分子刚度对膜锚定受体-配体结合动力学影响的理论与模拟研究

钟楚晗; 徐光魁

doi:10.21656/1000-0887.420262

分子刚度对膜锚定受体-配体结合动力学影响的理论与模拟研究

doi: 10.21656/1000-0887.420262

钟楚晗,
徐光魁^,

西安交通大学航天航空学院多尺度力学医学交叉实验室，西安 710049

基金项目:

国家自然科学基金（12072252）

详细信息

作者简介:
钟楚晗（1999—），女，硕士生(E-mail: zhongzhongchuhan@163.com);徐光魁（1986—），男，教授，博士，博士生导师(通讯作者. E-mail: guangkuixu@mail.xjtu.edu.cn).

通讯作者:
徐光魁（1986—），男，教授，博士，博士生导师(通讯作者. E-mail: guangkuixu@mail.xjtu.edu.cn).

中图分类号: O34
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- 文章访问数: 1146
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- 被引次数: 0
出版历程
- 收稿日期: 2021-09-02
- 修回日期: 2021-09-18
- 刊出日期: 2021-10-01

Theoretical and Simulation Studies on the Effect of Molecular Stiffness on Binding Kinetics of Membrane-Anchored Receptors And Ligands

ZHONG Chuhan,
XU Guangkui^,

Laboratory for Multiscale Mechanics and Medical Science, School of Aerospace Engineering, Xi’an Jiaotong University, Xi’an 710049, P.R.China

Funds:

The National Natural Science Foundation of China(12072252)

摘要

摘要: 人体内大部分生物学过程都离不开细胞黏附.细胞黏附行为主要由锚定于细胞膜上的特异性分子（又称受体和配体）的结合动力学关系来决定.已有研究表明，特异性分子的结合关系受外力及细胞膜波动等多种因素影响.然而，特异性分子刚度对细胞膜锚定受体配体结合关系的影响机制仍不清楚.近期关于新冠病毒强传染力的研究表明，特异性黏附分子刚度对病毒与细胞结合具有重要影响.该文通过建立生物膜黏附的粗粒度模型，借助分子模拟和理论分析来研究分子刚度在黏附中的作用.结果表明，始终存在一个最佳膜间距及最佳分子刚度值，使得黏附分子亲和力和结合动力学参数达到最大值.这项研究不仅能加深人们对细胞黏附的认知，还有助于指导药物设计、疫苗研发等.
- 分子刚度 /
- 亲和力 /
- 结合动力学 /
- 膜间距 /
- 细胞黏附
Abstract: Cell adhesion plays an important role in most biological processes in human body. Cell adhesion is mainly determined by the binding kinetics of specific molecules (called receptors and ligands) anchored on the cell membrane. Although it is known that the binding relation of specific molecules is affected by various factors as external forces and cell membrane fluctuations, it is still unclear how the molecular stiffness affects the binding relation between the membrane-anchored receptors and ligands. Recent studies on the strong infectivity of the coronavirus have shown the importance of specific molecular stiffness to the adhesion between virus and cells. Here, we develop a coarse-grained model of biomembrane adhesion, and use molecular simulation and theoretical analysis to reveal the role of molecular stiffness in adhesion. The results show that there is always an optimal membrane and an optimal molecular stiffness value, and the adhesion molecular affinity and binding kinetic parameters reach the maximum. This study can not only deepen the understanding of cell adhesion, but also help guide drug design and vaccine development.
- molecular stiffness /
- binding affinity /
- binding kinetics /
- membrane separation /
- cell adhesion

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参考文献(40)

[2]BURRIDGE K, CHRZANOWSKA-WODNICKA M. Focal adhesions, contractility, and signaling[J].Annual Review of Cell and Developmental Biology,1996,12(1): 463-519.

ALBERTS B, JOHNSON A, LEWIS J, et al.Molecular Biology of the Cell[M]. New York: Garland Science Press, 2002.

[3]GEIGER B, BERSHADSKY A, PANKOV R, et al. Transmembrane extracellular matrix-cytoskeleton crosstalk[J].Nature Reviews Molecular Cell Biology,2001,2(11): 793-805.

[4]XU G K, QIAN J, HU J. The glycocalyx promotes cooperative binding and clustering of adhesion receptors[J].Soft Matter,2016,12(20): 4572-4583.

[5]戎伟峰,王如彬. 耳蜗毛细胞活动的神经动力学分析[J]. 应用数学和力学，2019,40(2): 139-149.(PANG Weifeng, WANG Rubin. Neurodynamic analysis of cochlear hair cell activity[J].Applied Mathematics and Mechanics,2019,40(2):139-149.(in Chinese)）

[6]Bongrand P. Ligand-receptor interactions[J].Reports on Progress in Physics,1999,62(6): 921-968.

[7]WEIKL T R, ASFAW M, KROBATH H, et al. Adhesion of membranes via receptor-ligand complexes: domain formation, binding cooperativity, and active processes[J].Soft Matter,2009,5(17): 3213-3224.

[8]WU Y, VENDOME J, SHAPIRO L, et al. Transforming binding affinities from three dimensions to two with application to cadherin clustering[J].Nature,2011,475: 510-513.

[9]BELL G I. Models for the specific adhesion of cells to cells[J].Science,1978,200(4342): 618-627.

[10]DEMBO M, TORNEY D C, SAXMAN K, et al. The reaction-limited kinetics of membrane-to-surface adhesion and detachment[J].Proceedings of the Royal Society of London（Series B）: Biological Sciences,1988,234(1274): 55-83.

[11]ERDMANN T, SCHWARZ U S. Stability of adhesion clusters under constant force[J].Physical Review Letters,2004,92(10): 108102.

[12]HUPPA J B, AXMANN M, MORTELMAIER M A, et al. TCR-peptide-MHC interactions in situ show accelerated kinetics and increased affinity[J].Nature,2010,463(7283): 963-967.

[13]DUSTIN M L, BROMLEY S K, DAVIS M M, et al. Identification of self through two-dimensional chemistry and synapses[J].Annual Review of Cell and Developmental Biology,2001,17(1): 133-157.

[14]MILSTEIN O, TSENG S Y, STARR T, et al. Nanoscale increases in CD2-CD48-mediated intermembrane spacing decrease adhesion and reorganize the immunological synapse[J].Journal of Biological Chemistry,2008,283(49): 34414-34422.

[15]JEPPESEN C, WONG J Y, KUHL T L, et al. Impact of polymer tether length on multiple ligand-receptor bond formation[J].Science,2001,293(5529): 465-468.

[16]KROBATH H, ROZYCKI B, LIPOWSKY R, et al. Binding cooperativity of membrane adhesion receptors[J].Soft Matter,2009,5(17): 3354-3361.

[17]HU J, LIPOWSKY R, WEIKL T R. Binding constants of membrane-anchored receptors and ligands depend strongly on the nanoscale roughness of membranes[J].Proceedings of the National Academy of Sciences of the United States of America,2013,110(38): 15283-15288.

[18]MULIVOR A W, LIPOWSKY H H. Role of glycocalyx in leukocyte-endothelial cell adhesion[J].American Journal of Physiology-Heart and Circulatory Physiology,2002,283(4): H1282-H1291.

[19]PASZEK M J, DUFORT C C, ROSSIER O, et al. The cancer glycocalyx mechanically primes integrin-mediated growth and survival[J].Nature,2014,511(7509): 319-325.

[20]LONG M, GOLDSMITH H L, TEES D F J, et al. Probabilistic modeling of shear-induced formation and breakage of doublets cross-linked by receptor-ligand bonds[J].Biophysical Journal,1999,76(2): 1112-1128.

[21]MARSHALL B T, LONG M, PIPER J W, et al. Direct observation of catch bonds involving cell-adhesion molecules[J].Nature,2003,423(6936): 190-193.

[22]LONG M, CHEN J, JIANG N, et al. Probabilistic modeling of rosette formation[J].Biophysical Journal,2006,91(1): 352-363.

[23]XIAO B T, TONG C F, JIA X L, et al. Tyrosine replacement of PSGL-1 reduces association kinetics with P- and L-selectin on the cell membrane[J].Biophysical Journal,2012,103(4): 777-785.

[24]QIAN J, WANG J Z, GAO H J. Lifetime and strength of adhesive molecular bond clusters between elastic media[J].Langmuir,2008,24(4): 1262-1270.

[25]QIAN J, WANG J Z, LIN Y, et al. Lifetime and strength of periodic bond clusters between elastic media under inclined loading[J].Biophysical Journal,2009,97(9): 2438-2445.

[26]LIU B, QU M J, QIN K R, et al. Role of cyclic strain frequency in regulating the alignment of vascular smooth muscle cells in vitro[J].Biophysical Journal,2008,94(4): 1497-1507.

[27]KONG D, JI B H, DAI L H. Stability of adhesion clusters and cell reorientation under lateral cyclic tension[J].Biophysical Journal,2008,95(8): 4034-4044.

[28]KONG D, JI B H, DAI L H. Stabilizing to disruptive transition of focal adhesion response to mechanical forces[J].Journal of Biomechanics,2010,43(13): 2524-2529.

[29]HUANG J Y, QIN L, PENG X L, et al. Cellular traction force recovery: an optimal filtering approach in two-dimensional Fourier space[J].Journal of Theoretical Biology,2009,259(4): 811-819.

[30]FANG Y, WU J H, MCEVER R P, et al. Bending rigidities of cell surface molecules P-selectin and PSGL-1[J].Journal of Biomechanics,2009,42(3): 303-307.

[31]DU J, CHEN X F, LIANG X D, et al. Integrin activation and internalization on soft ECM as a mechanism of induction of stem cell differentiation by ECM elasticity[J].Proceedings of the National Academy of Sciences of the United States of America,2011,108(23): 9466-9471.

[32]XU G K, YANG C, DU J, et al. Integrin activation and internalization mediated by extracellular matrix elasticity: a biomechanical model[J].Journal of Biomechanics,2014,47(6): 1479-1484.

[33]BARROS E P, CASALINO L, GAIEB Z, et al. The flexibility of ACE2 in the context of SARS-CoV-2 infection[J].Biophysical Journal,2021,120(6): 1072-1084.

[34]KE Z L, OTON J, QU K, et al. Structures and distributions of SARS-CoV-2 spike proteins on intact virions[J].Nature,2020,588(7838): 498-502.

[35]SERAPIAN S A, COLOMBO G. Bow to the enemy: how flexibility of host protein receptors can favor SARS-CoV-2[J].Biophysical Journal,2021,120(6): 977-979.

[36]YAO H P, SONG Y T, CHEN Y, et al. Molecular architecture of the SARS-CoV-2 virus[J].Cell,2020,183(3): 730-738.

[37]TURONOVA B, SIKORA M, SCHURMANN C, et al. In situ structural analysis of SARS-CoV-2 spike reveals flexibility mediated by three hinges[J].Science,2020,370(6513): 203-208.

[38]XU G K, HU J L, LIPOWSKY R, et al. Binding constants of membrane-anchored receptors and ligands: a general theory corroborated by Monte-Carlo simulations[J].The Journal of Chemical Physics,2015,143(24): 243136.

[39]WEIKL T R, LIPOWSKY R. Membrane adhesion and domain formation[J].Advances in Planar Lipid Bilayers and Liposomes,2007,5(1): 63-127.

[40]BINDER K, CEPERLEY D M, HANSEN J P, et al.Monte-Carlo Methods in Statistical Physics[M]. Springer Science & Business Media, 2012.

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分子刚度对膜锚定受体-配体结合动力学影响的理论与模拟研究

doi: 10.21656/1000-0887.420262

作者简介:
钟楚晗（1999—），女，硕士生(E-mail: zhongzhongchuhan@163.com);徐光魁（1986—），男，教授，博士，博士生导师(通讯作者. E-mail: guangkuixu@mail.xjtu.edu.cn).

通讯作者:
徐光魁（1986—），男，教授，博士，博士生导师(通讯作者. E-mail: guangkuixu@mail.xjtu.edu.cn).

计量

Theoretical and Simulation Studies on the Effect of Molecular Stiffness on Binding Kinetics of Membrane-Anchored Receptors And Ligands

计量

目录

留言板

分子刚度对膜锚定受体-配体结合动力学影响的理论与模拟研究

doi: 10.21656/1000-0887.420262

作者简介: 钟楚晗（1999—），女，硕士生(E-mail: zhongzhongchuhan@163.com);徐光魁（1986—），男，教授，博士，博士生导师(通讯作者. E-mail: guangkuixu@mail.xjtu.edu.cn).

通讯作者: 徐光魁（1986—），男，教授，博士，博士生导师(通讯作者. E-mail: guangkuixu@mail.xjtu.edu.cn).

计量

出版历程

Theoretical and Simulation Studies on the Effect of Molecular Stiffness on Binding Kinetics of Membrane-Anchored Receptors And Ligands

计量

出版历程

目录

作者简介:
钟楚晗（1999—），女，硕士生(E-mail: zhongzhongchuhan@163.com);徐光魁（1986—），男，教授，博士，博士生导师(通讯作者. E-mail: guangkuixu@mail.xjtu.edu.cn).

通讯作者:
徐光魁（1986—），男，教授，博士，博士生导师(通讯作者. E-mail: guangkuixu@mail.xjtu.edu.cn).