Martinac Adam D, Bavi Navid, Bavi Omid, Martinac Boris
Molecular Cardiology and Biophysics Division, Victor Chang Cardiac Research Institute, Darlinghurst, NSW, Australia.
St Vincent's Clinical School, Faculty of Medicine, University of New South Wales, Darlinghurst, NSW, Australia.
PLoS One. 2017 Aug 31;12(8):e0183822. doi: 10.1371/journal.pone.0183822. eCollection 2017.
There are great opportunities in the manipulation of bacterial mechanosensitive (MS) ion channels for specific and targeted drug delivery purposes. Recent research has shown that these ion channels have the potential to be converted into nanovalves through clever use of magnetic nanoparticles and magnetic fields. Using a combination of molecular dynamics (MD) simulations and the finite element (FE) modelling, this study investigates the theoretical feasibility of opening the MscL channel (MS channel of large conductance of E. coli) by applying mechanical force directly to its N-terminus. This region has already been reported to function as a major mechanosensor in this channel. The stress-strain behaviour of each MscL helix was obtained using all atom MD simulations. Using the same method, we simulated two models, the wild-type (WT) MscL and the G22N mutant MscL, both embedded in a POPE lipid bilayer. In addition to indicating the main interacting residues at the hydrophobic pore, their pairwise interaction energies were monitored during the channel gating. We implemented these inputs into our FE model of MscL using curve-fitting codes and continuum mechanics equations. In the FE model, the channel could be fully opened via pulling directly on the N-terminus and bottom of TM1 by mutating dominant van der Waals interactions in the channel pore; otherwise the stress generated on the channel protein can irreversibly unravel the N-secondary structure. This is a significant finding suggesting that applying force in this manner is sufficient to open an MscL nanovalve delivering various drugs used, for example, in cancer chemotherapy. More importantly, the FE model indicates that to fully operate an MscL nanovalve by pulling directly on the N-terminus and bottom of TM1, gain-of-function (GOF) mutants (e.g., G22N MscL) would have to be employed rather than the WT MscL channel.
利用细菌机械敏感（MS）离子通道实现特定和靶向药物递送具有巨大潜力。最近的研究表明，通过巧妙利用磁性纳米颗粒和磁场，这些离子通道有潜力被转化为纳米阀。本研究结合分子动力学（MD）模拟和有限元（FE）建模，探讨了通过直接对大肠杆菌大电导MS通道（MscL通道）的N端施加机械力来打开该通道的理论可行性。该区域已被报道在该通道中起主要机械传感器的作用。使用全原子MD模拟获得了每个MscL螺旋的应力-应变行为。使用相同方法，我们模拟了两个模型，即野生型（WT）MscL和G22N突变型MscL，二者均嵌入POPE脂质双层中。除了指明疏水孔处的主要相互作用残基外，还在通道门控过程中监测了它们的成对相互作用能。我们使用曲线拟合代码和连续介质力学方程将这些输入数据应用于我们的MscL有限元模型。在有限元模型中，通过突变通道孔中的主要范德华相互作用，直接拉动TM1的N端和底部可使通道完全打开；否则，通道蛋白上产生的应力会不可逆地解开N二级结构。这一重要发现表明，以这种方式施加力足以打开一个MscL纳米阀，用于递送例如癌症化疗中使用的各种药物。更重要的是，有限元模型表明，要通过直接拉动TM1的N端和底部来完全操作一个MscL纳米阀，必须使用功能获得（GOF）突变体（例如G22N MscL），而不是WT MscL通道。
