Ionic strength effects on the association funnel of barnase and barstar investigated by Brownian dynamics simulations

Spaar, Alexander; Helms, Volkhard

doi:10.1016/j.jnoncrysol.2006.03.117

Cited by 7 publications

(6 citation statements)

References 22 publications

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“…Analysis of the effect of the mutations on the encounter complex showed that a single mutation could considerably alter the freeenergy landscape and change the population of the two minima (i.e., the two regions of the encounter complex). As expected for a charged protein-pair like barnase-barstar, the free-energy landscape was also affected by ionic strength (33).…”

Section: Introductionsupporting

confidence: 55%

Fruitful and Futile Encounters along the Association Reaction between Proteins

Harel

Spaar

Schreiber

2009

Biophysical Journal

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The association reaction between pairs of proteins proceeds through an encounter complex that develops into the final complex. Here, we combined Brownian dynamics simulations with experimental studies to analyze the structures of the encounter complexes along the association reaction between TEM1-beta-lactamase and its inhibitor, beta-lactamase-inhibitor protein. The encounter complex can be considered as an ensemble of short-lived low free-energy states that are stabilized primarily by electrostatic forces and desolvation. For the wild-type, the simulation showed two main encounter regions located outside the physical binding site. One of these regions was located near the experimentally determined transition state. To validate whether these encounters are fruitful or futile, we examined three groups of mutations that altered the encounter. The first group consisted of mutations that increased the experimental rate of association through electrostatic optimization. This resulted in an increase in the size of the encounter region located near the experimentally determined transition state, as well as a decrease in the energy of this region and an increase in the number of successful trajectories (i.e., encounters that develop into complex). A second group of mutations was specifically designed to either increase or decrease the size and energy of the second encounter complex, but either way it did not affect k(on). A third group of mutations consisted of residues that increased k(on) without significantly affecting the encounter complexes. These results indicate that the size and energy of the encounter regions are only two of several parameters that lead to fruitful association, and that electrostatic optimization is a major driving force in fast association.

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Section: Introductionsupporting

confidence: 55%

Fruitful and Futile Encounters along the Association Reaction between Proteins

Harel

Spaar

Schreiber

2009

Biophysical Journal

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“…8,10,11 Superimposing the Brownian dynamics analysis with the here generated transition state map shows that the "hot region" of the transition state superimposed well with the encounter complex region located above the interface, but not with the region mapped near the RNA binding site (Figure 8). According to Spaar et al, the two encounter complex regions differ in their energetics; the region above the interface is more favorable than the region above the RNA binding site, which seems to be not essential for the association.…”

Section: Mapping the Barnase-barstar Transition Statementioning

confidence: 90%

“…The pathways for association and dissociation of these two molecules were described as well. [7][8][9][10][11] Recently, Alsallaq and Zhou provided an alternative theoretical method for studying transient association complexes. Using a toy model of Barnase-Barstar, they showed that the transition state is close in space to the final complex, albeit with more degrees of freedom and only a few specific interactions.…”

Section: Introductionmentioning

confidence: 99%

On the Dynamic Nature of the Transition State for Protein–Protein Association as Determined by Double-mutant Cycle Analysis and Simulation

Harel

Cohen

Schreiber

2007

Journal of Molecular Biology

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“…The transient-complex ensemble separates the bound and unbound states of molecules. Although in case of protein–protein association the reaction criteria are typically straightforward, based on crystallographic structures of complexes and tuned versus experimental data, 48 , 53 , 93–95 it is not easy to define the reaction-criteria in the ribosome system. A major difficulty is that the ribosome is highly flexible 20 , 84 and characterizing the dynamical states of the ribosome with and without EF-G is, despite a lot of effort, 42 , 61 , 96–98 still to be completed.…”

Section: Methodsmentioning

confidence: 99%

Brownian dynamics study of the association between the 70S ribosome and elongation factor G

et al. 2011

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Protein synthesis on the ribosome involves a number of external protein factors that bind at its functional sites. One key factor is the elongation factor G (EF-G) that facilitates the translocation of transfer RNAs between their binding sites, as well as advancement of the messenger RNA by one codon. The details of the EF-G/ribosome diffusional encounter and EF-G association pathway still remain unanswered. Here, we applied Brownian dynamics methodology to study bimolecular association in the bacterial EF-G/70S ribosome system. We estimated the EF-G association rate constants at 150 and 300 mM monovalent ionic strengths and obtained reasonable agreement with kinetic experiments. We have also elucidated the details of EF-G/ribosome association paths and found that positioning of the L11 protein of the large ribosomal subunit is likely crucial for EF-G entry to its binding site. © 2011 Wiley Periodicals, Inc. Biopolymers 95: 616–627, 2011.

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Ionic strength effects on the association funnel of barnase and barstar investigated by Brownian dynamics simulations

Cited by 7 publications

References 22 publications

Fruitful and Futile Encounters along the Association Reaction between Proteins

Fruitful and Futile Encounters along the Association Reaction between Proteins

On the Dynamic Nature of the Transition State for Protein–Protein Association as Determined by Double-mutant Cycle Analysis and Simulation

Brownian dynamics study of the association between the 70S ribosome and elongation factor G

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