Prediction of Salt and Mutational Effects on the Association Rate of U1A Protein and U1 Small Nuclear RNA Stem/Loop II

Qin, Sanbo; Zhou, Huan‐Xiang

doi:10.1021/jp075919k

Cited by 23 publications

(75 citation statements)

References 76 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Two well-known ways for increasing the binding rate of a protein with a target are long-range electrostatic attraction, which increases the probability of reaching the transient complex, and nonspecific binding to the surface of the target, which reduces the dimensionality of the search space. Past work on electrostatic rate enhancement has focused on manipulating distal charges (6,7,(26)(27)(28)(29)(30)(31). The parallel results presented above on the binding of restrictocin with the ribosome and with the SRL RNA suggest a strategy for using electrostatic rate enhancement: By reshaping the binding interface, the transient complex can be placed into a region in configurational space where there is strong electrostatic attraction.…”

Section: Resultsmentioning

confidence: 97%

“…Atomic charges were mapped to grid points with the cubic B-spline discretization, with the chgm flag set to spl2. Following our previous studies on protein-protein and protein-RNA binding (6,7,36,37), the dielectric boundary was specified as the van der Waals surface by setting the srfm flag to mol and srad to 0.…”

Section: Methodsmentioning

confidence: 99%

“…Each The electrostatic contribution to the binding free energy of restrictocin with the ribosome was calculated as (6,7,36,37) ⌬G el ϭ G el ͑complex͒ Ϫ G el ͑ribosome͒ Ϫ G el ͑toxin͒ [5] where Gel is the total electrostatic free energy (Coulomb plus solvation) of a solute molecule. Here, ''complex'' refers to the restrictocin-ribosome native complex, as prepared above.…”

Section: Methodsmentioning

confidence: 99%

“…The procedure for generating the transient complex was described (6,7). Briefly, after mapping the energy landscape around the native complex in the 6-dimensional space of relative translation and rotation, the transient complex was identified with the outer boundary of the bound-state energy well (4).…”

Section: Generation Of Transient-complex Ensemble and Calculation Of mentioning

confidence: 99%

“…These two features are shared to a large extent by a related family, represented by ricin, known as ribosome-inactivating proteins (3). We have developed an approach, referred to as the transient-complex theory, for calculating absolute binding rate constants (4)(5)(6)(7). In this work the theory was applied to dissect the contributions to the high ribosome-binding rate of restrictocin, a close homolog of ␣-sarcin.…”

mentioning

confidence: 99%

See 4 more Smart Citations

Dissection of the high rate constant for the binding of a ribotoxin to the ribosome

Qin

Zhou

2009

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

View full text Add to dashboard Cite

Restrictocin belongs to a family of site-specific ribonucleases that kill cells by inactivating the ribosome. The restrictocin–ribosome binding rate constant was observed to exceed 1010 M−1 s−1. We have developed a transient-complex theory to model the binding rates of protein–protein and protein–RNA complexes. The theory predicts the rate constant as ka = ka0 exp(−ΔGel*/kBT), where ka0 is the basal rate constant for reaching the transient complex, located at the outer boundary of the bound state, by random diffusion, and ΔGel* is the average electrostatic interaction free energy of the transient complex. Here, we applied the transient-complex theory to dissect the high restrictocin–ribosome binding rate constant. We found that the binding rate of restrictocin to the isolated sarcin/ricin loop is electrostatically enhanced by ≈300-fold, similar to results found in other protein–protein and protein–RNA complexes. The ribosome provides an additional 10,000-fold rate enhancement because of two synergistic mechanisms afforded by the distal regions of the ribosome. First, they provide additional electrostatic attraction with restrictocin. Second, they reposition the transient complex into a region where local electrostatic interactions of restrictocin with the sarcin/ricin loop are particularly favorable. Our calculations rationalize a host of experimental observations and identify a strategy for designing proteins that bind their targets with high speed.

show abstract

Section: Resultsmentioning

confidence: 97%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Generation Of Transient-complex Ensemble and Calculation Of mentioning

confidence: 99%

mentioning

confidence: 99%

See 3 more Smart Citations

Dissection of the high rate constant for the binding of a ribotoxin to the ribosome

Qin

Zhou

2009

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

View full text Add to dashboard Cite

show abstract

Protein Recognition

Mansfield

Cross

Matthews

et al. 2009

Amino Acids, Peptides and Proteins in Organic Chemistry

View full text Add to dashboard Cite

Proteins function by making and breaking interactions with other molecules. The identities of these molecules cover the full spectrum of substances that one might find in an organism, illustrating the astounding structural and functional diversity that can be obtained from different combinations of roughly 20 amino acids. Thus, proteins are able to form functional interactions with partners ranging from metal ions and small diatomic molecules, such as oxygen and nitric oxide, through to typical organic molecules and macromolecules, such as nucleic acid polymers, polysaccharides, and of course other proteins. Given the enormous breadth of these interactions and the functions that they bring about, we have chosen in this chapter to focus on capturing a few of the general principles underlying protein recognition. As other chapters in this volume deal in depth with enzymes and enzyme-substrate interactions, we focus here on protein-protein and protein-DNA recognition.First, we discuss the general physicochemical nature of the interfaces made between proteins and their partners, the strength of these interactions, and methods for measuring their strength. Next, we describe two areas of protein recognition that have recently received much attention: coupled folding and binding, in which at least one of the partners in a protein interaction is disordered in the absence of its partner, and the regulation of protein interactions by post-translational modification (PTM) -a phenomenon that underlies diverse biological processes such as signaling and gene regulation. Finally, we look at progress that has been made in exploiting our understanding of protein recognition to either inhibit protein-protein interactions or to engineer new interactions for research or therapeutic purposes.

show abstract

U1A protein‐stem loop 2 RNA recognition: Prediction of structural differences from protein mutations

et al. 2011

View full text Add to dashboard Cite

Molecular dynamics (MD) simulations were carried out to compare the free and bound structures of wild type U1A protein with several Phe56 mutant U1A proteins that bind the target stem loop 2 (SL2) RNA with a range of affinities. The simulations indicate the free U1A protein is more flexible than the U1A-RNA complex for both wild type and Phe56 mutant systems. A complete analysis of the hydrogen bonding (HB) and non-bonded (VDW) interactions over the course of the MD simulations suggested that changes in the interactions in the free U1A protein caused by the Phe56Ala and Phe56Leu mutations may stabilize the helical character in loop 3, and contribute to the weak binding of these proteins to SL2 RNA. Compared to wild type, changes in HB and VDW interactions in Phe56 mutants of the free U1A protein are global, and include differences in β-sheet, loop 1 and loop 3 interactions. In the U1A-RNA complex, the Phe56Ala mutation leads to a series of differences in interactions that resonate through the complex, while the Phe56Leu and Phe56Trp mutations cause local differences around the site of mutation. The long-range networks of interactions identified in the simulations suggest that direct interactions and dynamic processes in both the free and bound forms contribute to complex stability.

show abstract

Prediction of Salt and Mutational Effects on the Association Rate of U1A Protein and U1 Small Nuclear RNA Stem/Loop II

Cited by 23 publications

References 76 publications

Dissection of the high rate constant for the binding of a ribotoxin to the ribosome

Dissection of the high rate constant for the binding of a ribotoxin to the ribosome

Protein Recognition

U1A protein‐stem loop 2 RNA recognition: Prediction of structural differences from protein mutations

Contact Info

Product

Resources

About