Functionally important correlated motions in the single-stranded DNA-binding protein encoded by filamentous phage Pf3

Horstink, Lennard M.; Abseher, Roger; Nilges, Michaël; Hilbers, Cornelis W.

doi:10.1006/jmbi.1999.2629

Cited by 21 publications

(17 citation statements)

References 35 publications

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“…For non-base-specific ssDNA interactions, OB folds retain flexibilities in its binding sites. hRPA70A, Pf3, T4gp32 and scRPA70A all show this common characteristic (51,54,55). The hydrogen bonding interaction between protein and ssDNA is also used in non-base-specific binding as well as in base-specific interaction.…”

Section: Discussionmentioning

confidence: 79%

Solution structure of the DNA-binding domain of RPA from Saccharomyces cerevisiae and its interaction with single-stranded DNA and SV40 T antigen

Park

2005

Nucleic Acids Research

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Replication protein A (RPA) is a three-subunit complex with multiple roles in DNA metabolism. DNA-binding domain A in the large subunit of human RPA (hRPA70A) binds to single-stranded DNA (ssDNA) and is responsible for the species-specific RPA–T antigen (T-ag) interaction required for Simian virus 40 replication. Although Saccharomyces cerevisiae RPA70A (scRPA70A) shares high sequence homology with hRPA70A, the two are not functionally equivalent. To elucidate the similarities and differences between these two homologous proteins, we determined the solution structure of scRPA70A, which closely resembled the structure of hRPA70A. The structure of ssDNA-bound scRPA70A, as simulated by residual dipolar coupling-based homology modeling, suggested that the positioning of the ssDNA is the same for scRPA70A and hRPA70A, although the conformational changes that occur in the two proteins upon ssDNA binding are not identical. NMR titrations of hRPA70A with T-ag showed that the T-ag binding surface is separate from the ssDNA-binding region and is more neutral than the corresponding part of scRPA70A. These differences might account for the species-specific nature of the hRPA70A–T-ag interaction. Our results provide insight into how these two homologous RPA proteins can exhibit functional differences, but still both retain their ability to bind ssDNA.

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Section: Discussionmentioning

confidence: 79%

Solution structure of the DNA-binding domain of RPA from Saccharomyces cerevisiae and its interaction with single-stranded DNA and SV40 T antigen

Park

2005

Nucleic Acids Research

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“…This includes both, membrane and nonmembrane proteins (46)(47)(48)(49)(50)(51)(52)(53)(54). However, as far as we know, this is the first case in which the analysis is performed after decomposing the atomic displacements into interchain and intrachain movements.…”

Section: Discussionmentioning

confidence: 99%

The Dynamic Behavior of the P2X4 Ion Channel in the Closed Conformation

Pierdominici‐Sottile

Moffatt

Palma

2016

Biophysical Journal

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We present the results of a detailed molecular dynamics study of the closed form of the P2X 4 receptor. The fluctuations observed in the simulations were compared with the changes that occur in the transition from the closed to the open structure. To get further insight on the opening mechanism, the actual displacements were decomposed into interchain motions and intrachain deformations. This analysis revealed that the iris-like expansion of the transmembrane helices mainly results from interchain motions that already take place in the closed conformation. However, these movements cannot reach the amplitude required for the opening of the channel because they are impeded by interactions occurring around the ATP binding pocket. This suggests that the union of ATP produces distortions in the chains that eliminate the restrictions on the interchain displacements, leading to the opening of the pore.

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“…One widely adopted approach uses a quasi-harmonic metric for correlations that assumes an “average” structure28, 29, 31-33. This approximation may be appropriate for small backbone fluctuations but may not aptly describe conformational changes that involve basin-hopping, such as loop or side-chain motions.…”

Section: Introductionmentioning

confidence: 99%

Quantifying Correlations Between Allosteric Sites in Thermodynamic Ensembles

McClendon

Friedland

Mobley

et al. 2009

J. Chem. Theory Comput.

215

284

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Allostery describes altered protein function at one site due to a perturbation at another site. One mechanism of allostery involves correlated motions, which can occur even in the absence of substantial conformational change. We present a novel method, "MutInf", to identify statistically significant correlated motions from equilibrium molecular dynamics simulations. Our approach analyzes both backbone and sidechain motions using internal coordinates to account for the gearlike twists that can take place even in the absence of the large conformational changes typical of traditional allosteric proteins. We quantify correlated motions using a mutual information metric, which we extend to incorporate data from multiple short simulations and to filter out correlations that are not statistically significant. Applying our approach to uncover mechanisms of cooperative small molecule binding in human interleukin-2, we identify clusters of correlated residues from 50 ns of molecular dynamics simulations. Interestingly, two of the clusters with the strongest correlations highlight known cooperative small-molecule binding sites and show substantial correlations between these sites. These cooperative binding sites on interleukin-2 are correlated not only through the hydrophobic core of the protein but also through a dynamic polar network of hydrogen bonding and electrostatic interactions. Since this approach identifies correlated conformations in an unbiased, statistically robust manner, it should be a useful tool for finding novel or "orphan" allosteric sites in proteins of biological and therapeutic importance.

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Functionally important correlated motions in the single-stranded DNA-binding protein encoded by filamentous phage Pf3

Cited by 21 publications

References 35 publications

Solution structure of the DNA-binding domain of RPA from Saccharomyces cerevisiae and its interaction with single-stranded DNA and SV40 T antigen

Solution structure of the DNA-binding domain of RPA from Saccharomyces cerevisiae and its interaction with single-stranded DNA and SV40 T antigen

The Dynamic Behavior of the P2X4 Ion Channel in the Closed Conformation

Quantifying Correlations Between Allosteric Sites in Thermodynamic Ensembles

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