Zipping and Unzipping of Adenylate Kinase: Atomistic Insights into the Ensemble of Open ↔ Closed Transitions

Beckstein, Oliver; Denning, Elizabeth J.; Perilla, Juan R.; Woolf, Thomas B.

doi:10.1016/j.jmb.2009.09.009

Cited by 142 publications

(250 citation statements)

References 78 publications

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“…Conformational transition pathways were generated using the BD algorithm discussed above together with a dynamic importance sampling algorithm incorporated to guide the simulation towards the target structure, instead of eigenvectors/eigenvalues obtained from ENM-NMA or MD-PCA 56,57 . The biasing function for the dynamic importance sampling was the sum of internal distances of the target structure.…”

Section: Methodsmentioning

confidence: 99%

Correlated motions are a fundamental property of β-sheets

et al. 2014

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Correlated motions in proteins can mediate fundamental biochemical processes such as signal transduction and allostery. The mechanisms that underlie these processes remain largely unknown due mainly to limitations in their direct detection. Here, based on a detailed analysis of protein structures deposited in the protein data bank, as well as on state-of-the art molecular simulations, we provide general evidence for the transfer of structural information by correlated backbone motions, mediated by hydrogen bonds, across b-sheets. We also show that the observed local and long-range correlated motions are mediated by the collective motions of b-sheets and investigate their role in large-scale conformational changes. Correlated motions represent a fundamental property of b-sheets that contributes to protein function.

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Section: Methodsmentioning

confidence: 99%

Correlated motions are a fundamental property of β-sheets

et al. 2014

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“…AdK is also well characterized structurally, with more than 50 crystal structures of AK eco and homologous proteins that range from closed to open conformations, suggestive of a sequence of intermediate conformations along a transition path [31,[46][47][48]. Out of these structures only four (PDB IDs 4ake, 2rh5, 3umf, 3gmt) were crystallized in the apo form, i.e.…”

Section: Adk As a Model For Macromolecular Conformational Transitionsmentioning

confidence: 99%

“…The enzyme AdK undergoes a large conformational change between a closed (left) and open (right) conformation, during which the LID domain (yellow) and NMP domain (blue) move relative to the CORE (gray). One choice of variables for quantifying the two bending motions is the LID-CORE angle (orange) and the NMP-CORE angle (purple) [31].…”

Section: Introductionmentioning

confidence: 99%

Sampling large conformational transitions: adenylate kinase as a testing ground

Seyler

Beckstein

2014

Molecular Simulation

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A fundamental problem in computational biophysics is to deduce the function of a protein from the structure. Many biological macromolecules such as enzymes, molecular motors, or membrane transport proteins perform their function by cycling between multiple conformational states. Understanding such conformational transitions, which typically occur on the millisecond to second time scale, is central to understanding protein function. Molecular dynamics (MD) computer simulations have become an important tool to connect molecular structure to function but equilibrium MD simulations are rarely able to sample on time scales longer than a few microseconds-orders of magnitudes shorter than the time scales of interest. A range of different simulation methods have been proposed to overcome this time-scale limitation. These include calculations of the free energy landscape and path sampling methods to directly sample transitions between known conformations. All these methods solve the problem to sample infrequently occupied but important regions of configuration space. Many path-sampling algorithms have been applied to the closed ↔ open transition of the enzyme adenylate kinase (AdK), which undergoes a large, clamshell-like conformational transition between an open and a closed state. Here we review approaches to sample macromolecular transitions through the lens of AdK. We focus our main discussion on the current state of knowledge-both from simulations and experiments-about the transition pathways of ligand-free AdK, its energy landscape, transition rates, and interactions with substrates. We conclude with a comparison of the discussed approaches with a view towards quantitative evaluation of path-sampling methods.

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“…Fig. 1B shows the contact energy distributions of the two sets of contacts for adenylate kinase, a model allosteric protein (10)(11)(12)(21)(22)(23)(24)(25)(26)(27)(28). To address the effects of sequence specificity unambiguously, we did not include interactions with ligands or substrates throughout this work.…”

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confidence: 99%

Frustration, specific sequence dependence, and nonlinearity in large-amplitude fluctuations of allosteric proteins

Wolynes

Takada

2011

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

154

185

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Proteins have often evolved sequences so as to acquire the ability for regulation via allosteric conformational change. Here we investigate how allosteric dynamics is designed through sequences with nonlinear interaction features. First, for 71 allosteric proteins of which two, open and closed, structures are available, a statistical survey of interactions using an all-atom model with effective solvation shows that those residue contact interactions specific to one of the two states are significantly weaker than are the contact interactions shared by the two states. This interaction feature indicates there is underlying sequence design to facilitate conformational change. Second, based on the energy landscape theory, we implement these interaction features into a new atomic-interaction-based coarse-grained model via a multiscale simulation protocol (AICG). The AICG model outperforms standard coarse-grained models for predictions of the native-state mean fluctuations and of the conformational change direction. Third, using the new model for adenylate kinase, we show that intrinsic fluctuations in one state contain rare and large-amplitude motions nearly reaching the other state. Such large-amplitude motions are realized partly by sequence specificity and partly by the nonlinear nature of contact interactions, leading to cracking. Both features enhance conformational transition rates.multiscale simulations | energy decomposition | allosteric motions | sequence design principle | interaction nonlinearity P roteins have evolved sequences that allow them to meet many requirements. For enzymes, two obvious requirements are foldability and catalytic ability. In the cellular context, a third requirement is regulation: Many proteins need to turn their activities on and off by changing conformation upon binding to their regulatory molecules or by posttranslational modification, i.e., the allosteric effect (1, 2). What are the design principles for meeting these requirements? It has been understood that foldability can be accomplished by having an overall funnel-like energy landscape: the principle of minimum frustration (3). Catalytic requirements seem to arise case-by-case, but precise spatial arrangement of catalytic residues is clearly of central importance. As for the third requirement of regulation, however, how sequences and structures are designed to facilitate conformational change is less clear. To enable conformational changes, proteins need to make relatively large-amplitude fluctuations toward specific directions. Here, we address the design principles for rotein allostery using an all-atom-based simplified force field.In native-basin dynamics, it has been well established that the quasi-harmonic fluctuations are encoded largely in the threedimensional architecture, as illustrated by the structure-based elastic network models (ENMs) (4-8). The relative root mean square fluctuations (RMSF) in the native state can be accurately reproduced by the Gaussian network model (5), a member of the ENM family. The directi...

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Zipping and Unzipping of Adenylate Kinase: Atomistic Insights into the Ensemble of Open ↔ Closed Transitions

Cited by 142 publications

References 78 publications

Correlated motions are a fundamental property of β-sheets

Correlated motions are a fundamental property of β-sheets

Sampling large conformational transitions: adenylate kinase as a testing ground

Frustration, specific sequence dependence, and nonlinearity in large-amplitude fluctuations of allosteric proteins

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