Analysis of <sup>15</sup>N–<sup>1</sup>H NMR Relaxation in Proteins by a Combined Experimental and Molecular Dynamics Simulation Approach: Picosecond–Nanosecond Dynamics of the Rho GTPase Binding Domain of Plexin-B1 in the Dimeric State Indicates Allosteric Pathways

Zerbetto, Mirco; Anderson, Ruth M.; Bouguet‐Bonnet, Sabine; Rech, Mariano; Zhang, Liqun; Meirovitch, Eva; Polimeno, Antonino; Buck, Matthias

doi:10.1021/jp310142f

Cited by 27 publications

(119 citation statements)

References 58 publications

(232 reference statements)

Supporting

Mentioning

113

Contrasting

Order By: Relevance

“…The reason is that in the current project, S 2 of three kinds of bonds (CH, NH, and CO) were considered, whereas in ref (18) only S 2 values of NH bonds were calculated. Because more side-chain bond dynamics were taken into consideration, it is not surprising to see the results are moderately different.…”

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

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

2014

Self Cite

View full text Add to dashboard Cite

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.

show abstract

Section: Resultsmentioning

confidence: 99%

“…Four molecular dynamics simulations were performed on plexin-B1 RBD dimer with the initial structure setup shown in detail in ref (18) also starting from the same dimer structure but with different random seeds in the NAMD simulations.…”

Section: Methodsmentioning

confidence: 99%

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

2014

Self Cite

View full text Add to dashboard Cite

show abstract

“…Only in the last few years have the design of special purpose machines and the development of algorithms made it possible to carry out fully atomistic simulations in solvent covering the millisecond time scale motions. This is the time scale for accessing truly distinct conformational minima as inferred from NMR ( Zerbetto et al 2013). Mere sampling of the structures of molten globules is also insufficient: it is necessary to quantify the solvent averaged free energies (not merely energies!)…”

Section: A License To Learn Via Bioinformatics: Structure Prediction mentioning

confidence: 99%

Frustration in biomolecules

Ferreiro

Komives

Wolynes

2014

Quart. Rev. Biophys.

268

295

View full text Add to dashboard Cite

Biomolecules are the prime information processing elements of living matter. Most of these inanimate systems are polymers that compute their own structures and dynamics using as input seemingly random character strings of their sequence, following which they coalesce and perform integrated cellular functions. In large computational systems with a finite interaction-codes, the appearance of conflicting goals is inevitable. Simple conflicting forces can lead to quite complex structures and behaviors, leading to the concept of frustration in condensed matter. We present here some basic ideas about frustration in biomolecules and how the frustration concept leads to a better appreciation of many aspects of the architecture of biomolecules, and how biomolecular structure connects to function. These ideas are simultaneously both seductively simple and perilously subtle to grasp completely. The energy landscape theory of protein folding provides a framework for quantifying frustration in large systems and has been implemented at many levels of description. We first review the notion of frustration from the areas of abstract logic and its uses in simple condensed matter systems. We discuss then how the frustration concept applies specifically to heteropolymers, testing folding landscape theory in computer simulations of protein models and in experimentally accessible systems. Studying the aspects of frustration averaged over many proteins provides ways to infer energy functions useful for reliable structure prediction. We discuss how frustration affects folding mechanisms. We review here how a large part of the biological functions of proteins are related to subtle local physical frustration effects and how frustration influences the appearance of metastable states, the nature of binding processes, catalysis and allosteric transitions. We hope to illustrate how Frustration is a fundamental concept in relating function to structural biology.

show abstract

“…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 …”

Section: Figurementioning

confidence: 99%

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

Zhang

Buck

2017

J. Phys. Chem. B

Self Cite

View full text Add to dashboard Cite

The Plexin family of transmembrane receptors are unique in that their intracellular region interacts directly with small GTPases of the Rho family. The Rho GTPase binding domain of plexin (RBD)—which is responsible for these interactions—can bind with Rac1 as well as Rnd1 GTPases. GTPase complexes have been crystallized with the RBDs of plexinA1, -A2, and -B1. The protein association is thought to elicit different functional responses in a GTPase and plexin isoform specific manner, but the origin of this is unknown. In this project, we investigated complexes between several RBD and Rac1/Rnd1 GTPases using multimicrosecond length all atom molecular dynamics simulations, also with reference to the free forms of the RBDs and GTPases. In accord with the crystallographic data, the RBDs experience more structural changes than Rho-GTPases upon complex formation. Changes in protein dynamics and networks of correlated motions are revealed by analyzing dihedral angle fluctuations in the proteins. The extent of these changes differs between the different RBDs and also between the Rac1 and Rnd1 GTPases. While the RBDs in the free and bound states have similar—if not decreased—correlations, correlations within the GTPases are increased upon binding. Mapping highly correlated residues to the structures, it is found that the plexinA1, -B1, and -A2 RBDs all have similar communication pathways within the ubiquitin fold, but that different residues are involved. Dynamic network analyses indicate that plexinA1 and -B1 RBDs interact with small GTPases in a similar manner, whereas complexes with the plexinA2 RBD display different features. Importantly complexes with Rnd1 have a considerable number of dynamic correlations and network connections between the proteins, whereas such features are missing in the RBD–Rac1 complexes. Overall, the simulations suggest mechanisms that are consistent with the experimental data on plexinB1 and indicate RBD and GTPase isoform specific changes in protein dynamics upon complex formation.

show abstract

Analysis of ¹⁵N–¹H NMR Relaxation in Proteins by a Combined Experimental and Molecular Dynamics Simulation Approach: Picosecond–Nanosecond Dynamics of the Rho GTPase Binding Domain of Plexin-B1 in the Dimeric State Indicates Allosteric Pathways

Cited by 27 publications

References 58 publications

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

Frustration in biomolecules

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

Contact Info

Product

Resources

About

Analysis of 15N–1H NMR Relaxation in Proteins by a Combined Experimental and Molecular Dynamics Simulation Approach: Picosecond–Nanosecond Dynamics of the Rho GTPase Binding Domain of Plexin-B1 in the Dimeric State Indicates Allosteric Pathways

Cited by 27 publications

References 58 publications

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

Frustration in biomolecules

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

Contact Info

Product

Resources

About

Analysis of ¹⁵N–¹H NMR Relaxation in Proteins by a Combined Experimental and Molecular Dynamics Simulation Approach: Picosecond–Nanosecond Dynamics of the Rho GTPase Binding Domain of Plexin-B1 in the Dimeric State Indicates Allosteric Pathways