Testing the transferability of a coarse-grained model to intrinsically disordered proteins

Rutter, Gil; Brown, Aaron H.; Quigley, David; Walsh, Tiffany R.; Allen, Michael

doi:10.1039/c5cp05652g

Cited by 23 publications

(22 citation statements)

References 83 publications

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“…After parametrization, it was demonstrated that the PLUM model folds several helical peptides, 14,23-26 stabilizes β-sheet structures, 14,15,[27][28][29] and is useful for probing the conformational variability of intrinsically disordered proteins. 30 We also considered two minor reparametrizations of the PLUM model: 1. The side chain van der Waals radius is decreased to 90% of its original value, 6 and 2.…”

Section: Plummentioning

confidence: 99%

Structural-Kinetic-Thermodynamic Relationships Identified from Physics-based Molecular Simulation Models

Rudzinski

Bereau

2017

Preprint

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Coarse-grained molecular simulation models have provided immense, often general, insight into the complex behavior of condensed-phase systems, but suffer from a lost connection to the true dynamical properties of the underlying system. In general, the physics that is built into a model shapes the free-energy landscape, restricting the attainable static and kinetic properties. In this work, we perform a detailed investigation into the property interrelationships resulting from these restrictions, for a representative system of the helix-coil transition. Inspired by high-throughput studies, we systematically vary force-field parameters and monitor their structural, kinetic, and thermodynamic properties. The focus of our investigation is a simple coarse-grained model, which accurately represents the underlying structural ensemble, i.e., effectively avoids sterically-forbidden configurations. As a result of this built-in physics, we observe a rather large restriction in the topology of the networks characterizing the simulation kinetics. When screening across force-field parameters, we find that structurally-accurate models also best reproduce the kinetics, suggesting structural-kinetic relationships for these models. Additionally, an investigation into thermodynamic properties reveals a link between the cooperativity of the transition and the network topology at a single reference temperature.

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Section: Plummentioning

confidence: 99%

Structural-Kinetic-Thermodynamic Relationships Identified from Physics-based Molecular Simulation Models

Rudzinski

Bereau

2017

Preprint

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“…The resulting data do not demonstrate any significant differences in the ensemble statistics of the two peptides when formed into oligomers. Structural differences reported previously [37] for the dimer do not persist into these larger aggregates. Conclusions regarding n16NN are somewhat more tentative than for n16N, as PLUM* data have not been validated against atomistic simulations for the mutant.…”

Section: Discussionmentioning

confidence: 67%

“…In the two-unit systems previously studied [37], a wholechain difference was seen in measures of conformational accessibility, including the frequency of interpeptide hydrogen bonds between n16N and n16NN, with the latter being higher. This led to the hypothesis that the whole-chain conformational accessibility, which may be a prerequisite of assembly, was compromised in the mutant.…”

Section: Resultsmentioning

confidence: 99%

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Emergence of order in self-assembly of the intrinsically disordered biomineralisation peptide n16N

Rutter

Brown

Quigley

et al. 2017

Molecular Simulation

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We present the results of an aggregation study on the intrinsically disordered biomineralisation peptide n16N, which selects the aragonite polymorph of calcium carbonate and is expected to have aggregationdependent structure and function. The peptide is a sub-sequence of the in vivo protein n16, with putative framework and polymorph selection roles in the nacre layer of pearl oyster (Pinctada fucata). Employing the intermediate-resolution coarse-grained protein model PLUM*, which has previously been validated with respect to n16N, we simulate assemblies of these peptide units for system sizes inaccessible to atomistic models. We use extensive conformational sampling to show that the configurational ensemble explored by n16N aggregates contains a significant proportion of ordered β-structure, within which arrangement of monomers is consistent with a previous hypothesis on functionally distinct subdomains of n16N. We also study an n16N mutant which fails to aggregate in experimental studies and obtain very similar behaviour, the consequences of which are discussed. ARTICLE HISTORY

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“…After parametrization, it was demonstrated that the PLUM model folds several helical peptides, 6,22-25 stabilizes βsheet structures, 6,[26][27][28][29] and is useful for probing the conformational variability of intrinsically disordered proteins. 30 We also considered 4 minor reparametrizations of the PLUM model:…”

Section: Plummentioning

confidence: 99%

The role of conformational entropy in the determination of structural-kinetic relationships for helix-coil transitions

Rudzinski

Bereau

2017

Preprint

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Coarse-grained molecular simulation models can provide significant insight into the complex behavior of protein systems, but suffer from an inherently distorted description of dynamical properties. We recently demonstrated that, for a heptapeptide of alanine residues, the structural and kinetic properties of a simulation model are linked in a rather simple way, given a certain level of physics present in the model. In this work, we extend these findings to a longer peptide, for which the representation of configuration space in terms of a full enumeration of sequences of helical/coil states along the peptide backbone is impractical. We verify the structural-kinetic relationships by scanning the parameter space of a simple native-biased model and then employ a distinct transferable model to validate and generalize the conclusions. Our results further demonstrate the validity of the previous findings, while clarifying the role of conformational entropy in the determination of the structural-kinetic relationships. More specifically, while the global, long timescale kinetic properties of a particular class of models with varying energetic parameters but approximately fixed conformational entropy are determined by the overarching structural features of the ensemble, a shift in these kinetic observables occurs for models with a distinct representation of steric interactions. At the same time, the relationship between structure and more local, faster kinetic properties is not affected by varying the conformational entropy of the model.

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Testing the transferability of a coarse-grained model to intrinsically disordered proteins

Cited by 23 publications

References 83 publications

Structural-Kinetic-Thermodynamic Relationships Identified from Physics-based Molecular Simulation Models

Structural-Kinetic-Thermodynamic Relationships Identified from Physics-based Molecular Simulation Models

Emergence of order in self-assembly of the intrinsically disordered biomineralisation peptide n16N

The role of conformational entropy in the determination of structural-kinetic relationships for helix-coil transitions

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