Backbone dynamics and energetics of a Calmodulin domain mutant exchanging between closed and open conformations

Evenäs, Johan; Forsén, Sture; Malmendal, Anders; Akke, Mikael

doi:10.1006/jmbi.1999.2770

Cited by 123 publications

(172 citation statements)

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“…Traditional molecular simulations are limited to Ͻ100 ns (2), making them inadequate to the task of studying large conformational transitions in macromolecules, which may occur on microsecond to millisecond time scales or beyond (3). Yet, the situation is actually worse than it first appears: even if such long simulations could be achieved, the observation of a single transition event would hardly be a full scientific description of the process.…”

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confidence: 99%

Efficient and verified simulation of a path ensemble for conformational change in a united-residue model of calmodulin

Zhang

Jasnow

Zuckerman

2007

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

121

165

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The computational sampling of rare, large-scale, conformational transitions in proteins is a well appreciated challenge-for which a number of potentially efficient path-sampling methodologies have been proposed. Here, we study a large-scale transition in a united-residue model of calmodulin using the ''weighted ensemble'' (WE) approach of Huber and Kim. Because of the model's relative simplicity, we are able to compare our results with bruteforce simulations. The comparison indicates that the WE approach quantitatively reproduces the brute-force results, as assessed by considering (i) the reaction rate, (ii) the distribution of event durations, and (iii) structural distributions describing the heterogeneity of the paths. Importantly, the WE method is readily applied to more chemically accurate models, and by studying a series of lower temperatures, our results suggest that the WE method can increase efficiency by orders of magnitude in more challenging systems.transition path ͉ path sampling ͉ weighted ensemble ͉ conformational transition

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mentioning

confidence: 99%

Efficient and verified simulation of a path ensemble for conformational change in a united-residue model of calmodulin

Zhang

Jasnow

Zuckerman

2007

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

121

165

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“…Instead, Eq. 4b is dominated by interactions with remote spins M. We estimated this contribution to 0 Ϯ 0.2 s Ϫ1 , based on the structures of closed and (Ca 2ϩ ) 2 forms of WT Tr2C (43) and a rotational correlation time of 4.2 ns (40). The maximum CSA͞CSA contribution was estimated to 0.035 and 0.51 s Ϫ1 for ␣-helices and ␤-strands, respectively, as calculated for a static magnetic field of 11.7 T and ⌬ values of 6.1 (␣-helices) and 27.1 (␤-strands) ppm (44).…”

Section: [3]mentioning

confidence: 99%

“…We have previously demonstrated that the calcium-loaded form of E140Q-Tr2C exchanges between two major conformations that resemble the calcium-loaded (open) and calcium-free (closed) states of WT Tr2C (11,39,40). Based on SQ 15 N, 1 H, and 13 C ␣ rotating-frame relaxation (R 1 ) measurements, the average exchange correlation times at 28°C are ͗ ex ͘ ϭ 22 Ϯ 7, 19 Ϯ 7, and 25 Ϯ 8 s, respectively, and the populations of the exchanging states are approximately equal (11,14,15).…”

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confidence: 99%

“…We recently reported a MQ relaxation study that monitored the correlated conformational exchange involving the 1 H and 15 N spins of each backbone amide group (19), which confirmed the previous 15 N relaxation results. However, both the temperature dependence and site-to-site variation of the residue-specific exchange correlation times, determined by using SQ 15 N, 1 H, and 13 C ␣ R 1 measurements, suggest that the conformational exchange may be more complex than a simple two-state process (11,14,15,40).…”

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confidence: 99%

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Correlated dynamics of consecutive residues reveal transient and cooperative unfolding of secondary structure in proteins

Lundström

Mulder

Akke

2005

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

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Nuclear spin relaxation is a powerful method for studying molecular dynamics at atomic resolution. Recent methods development in biomolecular NMR spectroscopy has enabled detailed investigations of molecular dynamics that are critical for biological function, with prominent examples addressing allostery, enzyme catalysis, and protein folding. Dynamic processes with similar correlation times are often detected in multiple locations of the molecule, raising the question of whether the underlying motions are correlated (corresponding to concerted fluctuations involving many atoms distributed across extended regions of the molecule) or uncorrelated (corresponding to independent fluctuations involving few atoms in localized regions). Here, we have used 13 C ␣ (i ؊ 1)͞ 13 C ␣ (i) differential multiple-quantum spin relaxation to provide direct evidence for correlated dynamics of consecutive amino acid residues in the protein sequence. By monitoring overlapping pairs of residues (i ؊ 1 and i, i and i ؉ 1, etc.), we identified correlated motions that extend through continuous segments of the sequence. We detected significant correlated conformational transitions in the native state of the E140Q mutant of the calmodulin C-terminal domain. Previous work has shown that this domain exchanges between two major conformational states that resemble the functionally relevant open and closed states of the WT protein, with a mean correlation time of Ϸ20 s. The present results reveal that an entire ␣-helix undergoes partial unraveling in a transient and cooperative manner.conformational exchange ͉ NMR ͉ nuclear spin relaxation P rotein dynamics are critical for biological function. Ligand binding, folding, and enzyme catalysis involve conformational dynamics covering a wide range of time scales and motional amplitudes (1-10). NMR spectroscopy is uniquely suited to study dynamic processes in biomolecules with atomic resolution, on time scales ranging from picoseconds to seconds. Chemical or conformational exchange processes that modify the local magnetic environments of nuclear spins on microsecond to millisecond time scales increase the relaxation rates of transverse magnetization (R 2 ), because they introduce a stochastic time dependence of the resonance frequencies. Relaxation dispersion experiments have been developed that quantify conformational exchange contributions to R 2 as a function of the strength of the applied radio-frequency fields, implemented either as CPMG (Carr-Purcell-Meiboom-Gill) pulse trains or continuous-wave spin-locks (8-10). In principle, NMR spectroscopy offers the possibility to monitor conformational exchange processes at every position along the protein backbone and side chains, provided that suitable stable isotopes (e.g., 13 C and 15 N) have been incorporated (4,(11)(12)(13)(14)(15). Importantly, the chemical shifts of different nuclei are sensitive to different types of intramolecular motions, which provides a major motivation for pursuing multinuclear studies of conformational exchange (14-21). Rec...

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“…It includes the backbone and the two hydrogen bonds formed by the residues in the 8 th position of binding loops (Ile27 and Ile63) and the C=O groups of the residues in the 7 th position of the binding loops (Thr26 and Thr62). 13 Indeed, in the absence of Ca 2+ , the N-terminal end of the binding loop is found to be poorly structured and very dynamic from NMR structures 11,14,15 and X-ray temperature factors. 12 Functional distinction between the two ends of the binding loops in the domain opening mechanism is buttressed by the great variability of the amino acid sequences of the N-terminal ends of the Ca 2+ -binding loops compared with the more conserved C-terminal ends across a variety of different EF-hand Ca 2+ -binding proteins.…”

Section: Introductionmentioning

confidence: 99%

Inherent flexibility and protein function: The open/closed conformational transition in the N-terminal domain of calmodulin

Tripathi

Portman

2008

The Journal of Chemical Physics

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Backbone dynamics and energetics of a Calmodulin domain mutant exchanging between closed and open conformations

Cited by 123 publications

References 0 publications

Efficient and verified simulation of a path ensemble for conformational change in a united-residue model of calmodulin

Efficient and verified simulation of a path ensemble for conformational change in a united-residue model of calmodulin

Correlated dynamics of consecutive residues reveal transient and cooperative unfolding of secondary structure in proteins

Inherent flexibility and protein function: The open/closed conformational transition in the N-terminal domain of calmodulin

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