Structure and dynamics analysis on plexin-B1 Rho GTPase binding domain as a monomer and dimer.
Structure and dynamics analysis on plexin-B1 Rho GTPase binding domain as a monomer and dimer.
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DOI：
10.1021/jp503668k
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发表时间：
2014-07-03
期刊：
影响因子：
--
通讯作者：
Buck M
中科院分区：
文献类型：
--
作者：
Zhang L;Centa T;Buck M
丛蛋白-B1是一种单向跨膜受体。它的Rho GTP酶结合结构域（RBD）可以与小Rho GTP酶结合，也可以自结合形成二聚体。总的来说，超过400 ns的NAMD分子动力学模拟进行RBD单体和二聚体。不同的分析方法，如均方根波动（RMSF），序参数（S2），二面角相关，转移熵，主成分分析，动力学网络分析，进行了表征的运动轨迹。RMSF结果表明，结合后，L4环变得更加刚性，但L2环和其他区域中的一些残基变得稍微更灵活。计算主链和侧链上CH、NH和CO键的序参数（S2）表明，L4环在结合后基本上变得刚性，但L1环的一部分变得稍微更灵活。骨架二面角互相关结果显示，与单体形式的其他区域相比，环区域如包括残基Q25和G26的L1环、包括残基R61的L2环和包括残基L 89-R91的L4环高度相关。在这些残基，如Q25和R61的相关运动的分析，表明两个信号通路。对RBD单体和二聚体形式的转移熵计算表明，结合过程应由L4环和C-末端驱动。然而，在绑定之后，L4循环用作运动响应器。基于动力学网络分析方法，使用二面角互相关计算预测的路径作为输入，预测RBD中的信号路径。发现从两个输入预测的最短通路可以重叠，但是信号通路2（从F90到R61）更占优势，并且与通路1（从F90到P111）的所有通路重叠。该项目证实了RBD网络内部信号传输的变构机制，这在以前的实验研究中部分提出。
Plexin-B1 is a single-pass transmembrane receptor. Its Rho GTPase binding domain (RBD) can associate with small Rho GTPases and can also self-bind to form a dimer. In total, more than 400 ns of NAMD molecular dynamics simulations were performed on RBD monomer and dimer. Different analysis methods, such as root mean squared fluctuation (RMSF), order parameters (S2), dihedral angle correlation, transfer entropy, principal component analysis, and dynamical network analysis, were carried out to characterize the motions seen in the trajectories. RMSF results show that after binding, the L4 loop becomes more rigid, but the L2 loop and a number of residues in other regions become slightly more flexible. Calculating order parameters (S2) for CH, NH, and CO bonds on both backbone and side chain shows that the L4 loop becomes essentially rigid after binding, but part of the L1 loop becomes slightly more flexible. Backbone dihedral angle cross-correlation results show that loop regions such as the L1 loop including residues Q25 and G26, the L2 loop including residue R61, and the L4 loop including residues L89–R91, are highly correlated compared to other regions in the monomer form. Analysis of the correlated motions at these residues, such as Q25 and R61, indicate two signal pathways. Transfer entropy calculations on the RBD monomer and dimer forms suggest that the binding process should be driven by the L4 loop and C-terminal. However, after binding, the L4 loop functions as the motion responder. The signal pathways in RBD were predicted based on a dynamical network analysis method using the pathways predicted from the dihedral angle cross-correlation calculations as input. It is found that the shortest pathways predicted from both inputs can overlap, but signal pathway 2 (from F90 to R61) is more dominant and overlaps all of the routes of pathway 1 (from F90 to P111). This project confirms the allosteric mechanism in signal transmission inside the RBD network, which was in part proposed in the previous experimental study.
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