Allostery and cooperativity revisited

Cui, Qiang; Karplus, Martin

doi:10.1110/ps.03259908

Cited by 610 publications

(599 citation statements)

References 104 publications

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“…Traditionally, allostery has been interpreted in terms of structural changes 3 or shifts in the populations of alternative conformations. 4 More recently it has been suggested that allostery may also be of dynamic origin with only marginal changes in average structure, [5][6][7][8][9] or that simultaneous changes in structure and dynamics play a significant role. 10 Driven by ongoing progress in experimental and theoretical methodology, there has been considerable effort to obtain a microscopic understanding of allosteric interactions and pathways.…”

Section: Introductionmentioning

confidence: 99%

Long-Range Conformational Transition of a Photoswitchable Allosteric Protein: Molecular Dynamics Simulation Study

et al. 2014

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A local perturbation of a protein may lead to functional changes at some distal site. An example is the PDZ2 domain of human tyrosine phosphatase 1E which shows an allosteric transition upon binding to a peptide ligand. Recently Buchli et al. presented a time-resolved study of this transition by covalently linking an azobenzene photoswitch across the binding groove and using a femtosecond laser pulse that triggers the cis-trans photoisomerization of azobenzene. To aid the interpretation of these experiments, in this work seven microsecond runs of all-atom molecular dynamics simulations each for the wild-type PDZ2 in the ligandbound and -free state, as well as the photoswitchable protein (PDZ2S) in the cis and the trans state of the photoswitch, in explicit water. First the theoretical model is validated by recalculating the available NMR data from the simulations. By comparing the results for PDZ2 and PDZ2S, it is analyzed to what extent the photoswitch indeed mimics the free-bound transition. A detailed description of the conformational rearrangement following the cis-trans photoisomerization of PDZ2S reveals a series of photoinduced structural changes, that propagate from the anchor residues of the photoswitch via intermediate secondary structure segments to the C-terminus of PDZ2S. The changes of the conformational distribution of the C-terminal region is considered as the distal response of the isolated allosteric protein. October 9, 2014 * To whom correspondence should be addressed 1 Abstract A local perturbation of a protein may lead to functional changes at some distal site. An example is the PDZ2 domain of human tyrosine phosphatase 1E which shows an allosteric transition upon binding to a peptide ligand. Recently Buchli et al. presented a time-resolved study of this transition by covalently linking an azobenzene photoswitch across the binding groove and using a femtosecond laser pulse that triggers the cis-trans photoisomerization of azobenzene. To aid the interpretation of these experiments, in this work seven microsecond runs of all-atom molecular dynamics simulations each for the wild-type PDZ2 in the ligandbound and -free state, as well as the photoswitchable protein (PDZ2S) in the cis and the trans state of the photoswitch, in explicit water. First the theoretical model is validated by recalculating the available NMR data from the simulations. By comparing the results for PDZ2 and PDZ2S, it is analyzed to what extent the photoswitch indeed mimics the free-bound transition. A detailed description of the conformational rearrangement following the cis-trans photoisomerization of PDZ2S reveals a series of photoinduced structural changes, that propagate from the anchor residues of the photoswitch via intermediate secondary structure segments to the C-terminus of PDZ2S. The changes of the conformational distribution of the C-terminal region is considered as the distal response of the isolated allosteric protein.

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Section: Introductionmentioning

confidence: 99%

Long-Range Conformational Transition of a Photoswitchable Allosteric Protein: Molecular Dynamics Simulation Study

et al. 2014

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“…GroEL is an extensively studied bacterial chaperonin that assists polypeptide chains in folding to form their native structure [84][85][86][87][88][89]. Figure 6C), whereas other † Correlation analysis performed using the alpha carbon positions of the reference atomic structure (PDB ID 1OEL) yields identical results to correlation analysis performed using FE nodes.…”

Section: Groelmentioning

confidence: 93%

“…These high inter-subunit correlations may be important for the cooperative ATP binding and hydrolysis reactions that occur in seven subunits within each ring with the heptameric symmetry of GroEL being maintained [84,86,89]. In contrast, all non-neighboring cluster pairs exhibit relatively low correlations.…”

Section: Groelmentioning

confidence: 99%

Conformational dynamics of supramolecular protein assemblies

Kim

Nguyen

Bathe

2011

Journal of Structural Biology

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Supramolecular protein assemblies including molecular motors, cytoskeletal filaments, chaperones, and ribosomes play a central role in a broad array of cellular functions ranging from cell division and motility to RNA and protein synthesis and folding. Single-particle reconstructions of such assemblies have been growing rapidly in recent years, providing increasingly high resolution structural information under native conditions. While the static structure of these assemblies provides essential insight into their mechanism of biological function, their dynamical motions provide additional important information that cannot be inferred from structure alone. Here we present an unsupervised computational framework for the analysis of high molecular weight assemblies and use it to analyze the conformational dynamics of structures deposited in the Electron Microscopy Data Bank. Protein assemblies are modeled using a recently introduced coarse-grained modeling framework based on the finite element method, which is used to compute equilibrium thermal fluctuations, elastic strain energy distributions associated with specific conformational transitions, and dynamical correlations in distant molecular domains. Results are presented in detail for the ribosome-bound termination factor RF2 from Escherichia coli, the nuclear pore complex from Dictyostelium discoideum, and the chaperonin GroEL from E. coli. Elastic strain energy distributions reveal hinge-regions associated with specific conformational change pathways, and correlations in collective molecular motions reveal dynamical coupling between distant molecular domains that suggest new, as well as confirm existing, allosteric mechanisms. Results are publically available for use in further investigation and interpretation of biological function including cooperative transitions, allosteric communication, and molecular mechanics, as well as in further classification and refinement of electron microscopy based structures.

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“…The N × c indicator matrix H encodes the membership in the partition, while the 1 × N vector π = (π (1) , . .…”

Section: Construction Of the Atomistic Networkmentioning

confidence: 99%

“…Allostery describes the widely observed phenomenon by which a perturbation at one site of a protein has a functional effect at another, distant site 1 . Traditionally, studies of allostery have been linked to the cooperativity observed in large multimeric proteins such as haemoglobin.…”

Section: Introductionmentioning

confidence: 99%

Uncovering allosteric pathways in caspase-1 using Markov transient analysis and multiscale community detection

et al. 2014

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Allosteric regulation at distant sites is central to many cellular processes. In particular, allosteric sites in proteins are a major target to increase the range and selectivity of new drugs, and there is a need for methods capable of identifying intra-molecular signalling pathways leading to allosteric effects. Here, we use an atomistic graph-theoretical approach that exploits Markov transients to extract such pathways and exemplify our results in an important allosteric protein, caspase-1. Firstly, we use Markov Stability community detection to perform a multiscale analysis of the structure of caspase-1 which reveals that the active conformation has a weaker, less compartmentalised large-scale structure as compared to the inactive conformation, resulting in greater intra-protein coherence and signal propagation. We also carry out a full computational point mutagenesis and identify that only a few residues are critical to such structural coherence. Secondly, we characterise explicitly the transients of random walks originating at the active site and predict the location of a known allosteric site in this protein quantifying the contribution of individual bonds to the communication pathway between the active and allosteric sites. Several of the bonds we find have been shown experimentally to be functionally critical, but we also predict a number of as yet unidentified bonds which may contribute to the pathway. Our approach offers a computationally inexpensive method for the identification of allosteric sites and communication pathways in proteins using a fully atomistic description.

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Allostery and cooperativity revisited

Cited by 610 publications

References 104 publications

Long-Range Conformational Transition of a Photoswitchable Allosteric Protein: Molecular Dynamics Simulation Study

Long-Range Conformational Transition of a Photoswitchable Allosteric Protein: Molecular Dynamics Simulation Study

Conformational dynamics of supramolecular protein assemblies

Uncovering allosteric pathways in caspase-1 using Markov transient analysis and multiscale community detection

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