Locally Distributed Tension Molecular Dynamics Approach

被引:17
作者
Rajeshwar, Rajitha T. [1 ]
Anishkin, Andriy [2 ]
Sukharev, Sergei [2 ]
Vanegas, Juan M. [1 ]
机构
[1] Univ Vermont, Dept Phys, Burlington, VT 05405 USA
[2] Univ Maryland, Dept Biol, College Pk, MD USA
基金
美国国家科学基金会;
关键词
CONDUCTANCE MECHANOSENSITIVE CHANNEL; OF-FUNCTION MUTATIONS; ION-CHANNEL; ESCHERICHIA-COLI; MSCL CHANNEL; FREE-ENERGY; MYCOBACTERIUM-TUBERCULOSIS; GATING MECHANISMS; MEMBRANE-TENSION; PORE-FORMATION;
D O I
10.1016/j.bpj.2020.11.2274
中图分类号
Q6 [生物物理学];
学科分类号
071011 ;
摘要
Membrane tension perceived by mechanosensitive (MS) proteins mediates cellular responses to mechanical stimuli and osmotic stresses, and it also guides multiple biological functions including cardiovascular control and development. In bacteria, MS channels function as tension-activated pores limiting excessive turgor pressure, with MS channel of large conductance (MscL) acting as an emergency release valve preventing cell lysis. Previous attempts to simulate gating transitions in MscL by either directly applying steering forces to the protein or by increasing the whole-system tension were not fully successful and often disrupted the integrity of the system. We present a novel, to our knowledge, locally distributed tension molecular dynamics (LDT-MD) simulation method that allows application of forces continuously distributed among lipids surrounding the channel using a specially constructed collective variable. We report reproducible and reversible transitions of MscL to the open state with measured parameters of lateral expansion and conductivity that exactly satisfy experimental values. The LDT-MD method enables exploration of the MscL-gating process with different pulling velocities and variable tension asymmetry between the inner and outer membrane leaflets. We use LDT-MD in combination with well-tempered metadynamics to reconstruct the tension-dependent free-energy landscape for the opening transition in MscL. The flexible definition of the LDT collective variable allows general application of our method to study mechanical activation of any membrane-embedded protein.
引用
收藏
页码:232 / 242
页数:11
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