Structure and Dynamics Analysis on Plexin-B1 Rho GTPase Binding Domain as a Monomer and Dimer

Abstract

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.

Molecular Dynamics Simulations Reveal Isoform Specific Contact Dynamics between the Plexin Rho GTPase Binding Domain (RBD) and Small Rho GTPases Rac1 and Rnd1

“…A dynamic network analysis was performed on the three RBDs in both the free and bound forms to find out possible communication pathways which connect these residues. We followed the same dynamic network analysis method and settings as in ref 29 (see also Materials and Methods Section). The results are shown in Figure S9.…”

“…29 An issue with any correlation analysis is that there has to be considerable dynamics and also changes in dynamics to make them visible/stand out above the noise. This, therefore, confines the analyses to the most dynamic regions of the proteins, such as the RBD loops (L1–L4) and the GTPase Switch regions (SW I and II).…”

“…29 The network model was built by the NetworkView plugin of VMD 37 and the program Carma. 38 In the network, nodes are single atoms or clusters of atoms, but here each Ca was treated as one node.…”

“…Blue and red arrows show the possible communication pathway 1 and pathway 2 which were originally found for the unbound plexin-B1 RBD in the previous work. 28,29 …”

Different dynamics and pathway of disulfide bonds reduction of two human defensins, a molecular dynamics simulation study

“…In recent years, molecular dynamics simulations have been proven to be a useful tool to understand the structure, dynamics and functional mechanism of proteins . Researchers have worked on the biophysical aspects of disulfide bonds containing proteins, and the link between conformational folding and disulfide bond formation/rupture using simulation method.…”