Long-range energy transfer in proteins

Piazza, Francesco; Sanejouand, Yves‐Henri

doi:10.1088/1478-3975/6/4/046014

Cited by 58 publications

(89 citation statements)

References 68 publications

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“…Long range non-additivity is expected in allosteric proteins (50) but also is common in many protein classes (51). In addition, energy in a protein can jump from site to site, covering large distances (52). A complex arrangement of interactions between distant amino acids is prevalent.…”

Section: Discussionmentioning

confidence: 99%

Allostery Wiring Map for Kinesin Energy Transduction and its Evolution

Richard

Kim

Nguyen

et al. 2017

Biophysical Journal

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How signals between the kinesin active and cytoskeletal binding sites are transmitted is an open question and an allosteric question. By extracting correlated evolutionary changes within 700؉ sequences, we built a model of residues that are energetically coupled and that define molecular routes for signal transmission. Typically, these coupled residues are located at multiple distal sites and thus are predicted to form a complex, non-linear network that wires together different functional sites in the protein. Of note, our model connected the site for ATP hydrolysis with sites that ultimately utilize its free energy, such as the microtubule-binding site, drug-binding loop 5, and necklinker. To confirm the calculated energetic connectivity between non-adjacent residues, double-mutant cycle analysis was conducted with 22 kinesin mutants. There was a direct correlation between thermodynamic coupling in experiment and evolutionarily derived energetic coupling. We conclude that energy transduction is coordinated by multiple distal sites in the protein rather than only being relayed through adjacent residues. Moreover, this allosteric map forecasts how energetic orchestration gives rise to different nanomotor behaviors within the superfamily.Biological motors function by converting the chemical energy of ATP hydrolysis into mechanical work in the cell. Thus, molecular motors are free energy transducers, i.e. free energy from the active site is redistributed through the motor protein and ultimately produces a new protein conformational state. Diverse microtubule (MT)-based 2 functions arise in part from differences in their mechanotransduction cycle. For example, members of certain kinesin families are capable of transporting cargo, whereas others modify the MT track (reviewed in Ref. 1).Our goal here is identification of key residues that choreograph transduction between the active site and the microtubule-binding site (see Fig. 1A). It is anticipated that this set of residues couples components that catalyze the free energy-donating reaction with the free energy-accepting ones that result in directed motion. Furthermore, this wiring network should be shared among kinesins and predict adjustment of mechanotransduction between motor families. Such knowledge would reveal mutations that can be used to systematically tune motor protein function.By definition, mechanotransduction is one form of allostery, given that its quintessential property is long range communication. Long range effects in kinesin have been reported. In the first type of study, allosteric mechanisms are inferred from comparisons of well populated conformational states (2, 3) and are primarily descriptive. In the second, molecular dynamics calculations describe dynamic properties of motor proteins as thermally stochastic and yet asymmetric (see Fig. 1B; reviewed in Refs. 4 -6). Theoretical treatments of allostery in other systems also show promise in uncovering fundamental principles of energy conversion, such as the idea that energy storage and transmi...

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Section: Discussionmentioning

confidence: 99%

Allostery Wiring Map for Kinesin Energy Transduction and its Evolution

Richard

Kim

Nguyen

et al. 2017

Biophysical Journal

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“…This process is accompanied by large structural rearrangements if there is an energy exchange between protein regions with "discrete breathers" (localized excitations). [28][29][30][31] The conformational selection paradigm implies that "discrete breathers" should be located close to ligand-binding sites. Although at first sight, the conformational selection paradigm and the approach that we used in this study look different, the similarity between them becomes clear if we make an analogy between "discrete breathers" and the eigenmodes of the burial mode model energy function 12 -in both descriptions, ligand-binding suppresses one mode and stimulates another, coupling large scale motions to the transduction of small forces.…”

Section: Discussionmentioning

confidence: 99%

Quantitative theory of hydrophobic effect as a driving force of protein structure

Perunov

England

2014

Protein Science

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Various studies suggest that the hydrophobic effect plays a major role in driving the folding of proteins. In the past, however, it has been challenging to translate this understanding into a predictive, quantitative theory of how the full pattern of sequence hydrophobicity in a protein shapes functionally important features of its tertiary structure. Here, we extend and apply such a phenomenological theory of the sequence-structure relationship in globular protein domains, which had previously been applied to the study of allosteric motion. In an effort to optimize parameters for the model, we first analyze the patterns of backbone burial found in singledomain crystal structures, and discover that classic hydrophobicity scales derived from bulk physicochemical properties of amino acids are already nearly optimal for prediction of burial using the model. Subsequently, we apply the model to studying structural fluctuations in proteins and establish a means of identifying ligand-binding and protein-protein interaction sites using this approach.

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“…Using an anharmonic model, it was shown that "discrete breathers", localized vibrational modes easily form in proteins at the stiffest regions, and are able to pump and store energy from neighboring sites. Thus, energy can 'jump' from site to site via this mechanism, often covering long distances [119,120]. In a Gaussian network model, the correlations between the energy fluctuations of residues were calculated, and were found to define an interaction pathway which was similar to the pathway defined by the co-evolving network of residues in the PDZ domain [121].…”

Section: Energy Propagation In Proteinsmentioning

confidence: 99%

Allo-Network Drugs: Extension of the Allosteric Drug Concept to Protein- Protein Interaction and Signaling Networks

Szilágyi¹,

Nussinov²,

Csermely

2013

CTMC

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Allosteric drugs are usually more specific and have fewer side effects than orthosteric drugs targeting the same protein. Here, we overview the current knowledge on allosteric signal transmission from the network point of view, and show that most intra-protein conformational changes may be dynamically transmitted across protein-protein interaction and signaling networks of the cell. Allo-network drugs influence the pharmacological target protein indirectly using specific inter-protein network pathways. We show that allo-network drugs may have a higher efficiency to change the networks of human cells than those of other organisms, and can be designed to have specific effects on cells in a diseased state. Finally, we summarize possible methods to identify allo-network drug targets and sites, which may develop to a promising new area of systems-based drug design.

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Long-range energy transfer in proteins

Cited by 58 publications

References 68 publications

Allostery Wiring Map for Kinesin Energy Transduction and its Evolution

Allostery Wiring Map for Kinesin Energy Transduction and its Evolution

Quantitative theory of hydrophobic effect as a driving force of protein structure

Allo-Network Drugs: Extension of the Allosteric Drug Concept to Protein- Protein Interaction and Signaling Networks

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