Counterbalance of ligand‐ and self‐coupled motions characterizes multispecificity of ubiquitin

DasGupta, Bhaskar; Nakamura, Haruki; Kinjo, Akira R.

doi:10.1002/pro.2195

Cited by 8 publications

(22 citation statements)

References 55 publications

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“…Such atomic packing may cause unrealistic fluctuations of the surface atoms. We observed significantly high surface fluctuations in our previous study [12]. The unrealistic fluctuations of surface atoms were also observed by Wako and Endo using only dihedral angles as variables rather than all Cartesian coordinates [13].…”

Section: Introductionsupporting

confidence: 75%

Specific Non-Local Interactions Are Not Necessary for Recovering Native Protein Dynamics

et al. 2014

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The elastic network model (ENM) is a widely used method to study native protein dynamics by normal mode analysis (NMA). In ENM we need information about all pairwise distances, and the distance between contacting atoms is restrained to the native value. Therefore ENM requires O(N2) information to realize its dynamics for a protein consisting of N amino acid residues. To see if (or to what extent) such a large amount of specific structural information is required to realize native protein dynamics, here we introduce a novel model based on only O(N) restraints. This model, named the ‘contact number diffusion’ model (CND), includes specific distance restraints for only local (along the amino acid sequence) atom pairs, and semi-specific non-local restraints imposed on each atom, rather than atom pairs. The semi-specific non-local restraints are defined in terms of the non-local contact numbers of atoms. The CND model exhibits the dynamic characteristics comparable to ENM and more correlated with the explicit-solvent molecular dynamics simulation than ENM. Moreover, unrealistic surface fluctuations often observed in ENM were suppressed in CND. On the other hand, in some ligand-bound structures CND showed larger fluctuations of buried protein atoms interacting with the ligand compared to ENM. In addition, fluctuations from CND and ENM show comparable correlations with the experimental B-factor. Although there are some indications of the importance of some specific non-local interactions, the semi-specific non-local interactions are mostly sufficient for reproducing the native protein dynamics.

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Section: Introductionsupporting

confidence: 75%

Specific Non-Local Interactions Are Not Necessary for Recovering Native Protein Dynamics

et al. 2014

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“…In a previous analysis by Ishida et al ., it was shown that the total coupled motions of the subunits in the subtilisin–eglin C complex are greatly influenced by their rigid‐body motions. Moreover, in our previous analysis, we observed that the characteristics of coupled rigid‐body motions in ubiquitin complexes greatly influence the complementarity at the interface . These analyses indicate the importance of studying rigid‐body motions in further detail.…”

Section: Introductionmentioning

confidence: 75%

“…Previously, we defined a multiligand interface that integrates all the interfaces on a date hub protein, and we also defined “overlapping” or “OV” and “nonoverlapping” or “non‐OV” regions in the multiligand interface based on the promiscuity of the interface sites . In a recent study, we observed that ligand‐coupled vibrational dynamics at the OV and non‐OV regions dictate conformational change due to binding, and therefore correlated to the multispecificity . However, we did not consider how the rigid‐body motions of a date hub protein (or receptor) and its ligands are directly correlated to such multispecificity.…”

Section: Introductionmentioning

confidence: 99%

“…For a dimeric protein complex (“RL,” where “R” and “L” are the receptor and ligand subunits) consisting of N atoms one obtains 3 N – 6 vibrational modes from AA‐NMA. These 3 N – 6 modes include 3 N R – 6 vibrational modes obtained from the receptor subunit “R” of N R atoms, 3 N L – 6 vibrational modes obtained from the ligand subunit “L” of N L atoms, and six modes characterizing the relative rigid‐body motions of the subunit “R” with respect to the subunit “L” . The coupling of 3 N R – 6 motions of the receptor to the 3 N L – 6 motions of the ligand and six relative rigid‐body motions are embedded in a rectangular submatrix of the covariance matrix yielded by the AA‐NMA.…”

Section: Introductionmentioning

confidence: 99%

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Rigid‐body motions of interacting proteins dominate multispecific binding of ubiquitin in a shape‐dependent manner

2013

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To understand the dynamic aspects of multispecificity of ubiquitin, we studied nine ubiquitin-ligand (partner protein) complexes by normal mode analysis based on an elastic network model. The coupling between ubiquitin and ligand motions was analyzed by decomposing it into rigid-body (external) and vibrational (internal) motions of each subunit. We observed that in total the external motions in one of the subunits largely dominated the coupling. The combination of external motions of ubiquitin and the ligands showed general trends of rotations and translations. Moreover, we observed that the rotational motions of ubiquitin were correlated to the ligand orientations. We also identified ubiquitin atomic vibrations that differentiated the orientation of the ligand molecule. We observed that the extents of coupling were correlated to the shapes of the ligands, and this trend was more pronounced when the coupling involved vibrational motions of the ligand. In conclusion, an intricate interplay between internal and external motions of ubiquitin and the ligands help understand the dynamics of multispecificity, which is mostly guided by the shapes of the ligands and the complex.

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“…In the first approach, we use the diagonal submatrix

that captures induced motions of each protein without considerations of induced motions of its binding partner or the coupling between the two sets of protein motions. The matrix is projected with the procedure described above [akin to the projection of the covariance matrix in Dasgupta et al (2013) ], and eigenvalues and eigenvectors are calculated with eigenvectors ranked with increasing eigenvalues (six eigenvectors corresponding to zero-valued eigenvalues are trivial normal modes corresponding to rigid-body motions and thus removed). In the second approach, the complex-derived Hessian matrix

is used for projection and eigen calculations, and the component of non-trivial normal modes corresponding to a protein under investigation is extracted.…”

Section: Methodsmentioning

confidence: 99%

cNMA: a framework of encounter complex-based normal mode analysis to model conformational changes in protein interactions

Oliwa

Shen

2015

Bioinformatics

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Motivation: It remains both a fundamental and practical challenge to understand and anticipate motions and conformational changes of proteins during their associations. Conventional normal mode analysis (NMA) based on anisotropic network model (ANM) addresses the challenge by generating normal modes reflecting intrinsic flexibility of proteins, which follows a conformational selection model for protein–protein interactions. But earlier studies have also found cases where conformational selection alone could not adequately explain conformational changes and other models have been proposed. Moreover, there is a pressing demand of constructing a much reduced but still relevant subset of protein conformational space to improve computational efficiency and accuracy in protein docking, especially for the difficult cases with significant conformational changes.Method and results: With both conformational selection and induced fit models considered, we extend ANM to include concurrent but differentiated intra- and inter-molecular interactions and develop an encounter complex-based NMA (cNMA) framework. Theoretical analysis and empirical results over a large data set of significant conformational changes indicate that cNMA is capable of generating conformational vectors considerably better at approximating conformational changes with contributions from both intrinsic flexibility and inter-molecular interactions than conventional NMA only considering intrinsic flexibility does. The empirical results also indicate that a straightforward application of conventional NMA to an encounter complex often does not improve upon NMA for an individual protein under study and intra- and inter-molecular interactions need to be differentiated properly. Moreover, in addition to induced motions of a protein under study, the induced motions of its binding partner and the coupling between the two sets of protein motions present in a near-native encounter complex lead to the improved performance. A study to isolate and assess the sole contribution of intermolecular interactions toward improvements against conventional NMA further validates the additional benefit from induced-fit effects. Taken together, these results provide new insights into molecular mechanisms underlying protein interactions and new tools for dimensionality reduction for flexible protein docking.Availability and implementation: Source codes are available upon request.Contact: yshen@tamu.edu

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Counterbalance of ligand‐ and self‐coupled motions characterizes multispecificity of ubiquitin

Cited by 8 publications

References 55 publications

Specific Non-Local Interactions Are Not Necessary for Recovering Native Protein Dynamics

Specific Non-Local Interactions Are Not Necessary for Recovering Native Protein Dynamics

Rigid‐body motions of interacting proteins dominate multispecific binding of ubiquitin in a shape‐dependent manner

cNMA: a framework of encounter complex-based normal mode analysis to model conformational changes in protein interactions

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