Thermodynamic analysis of structural transitions during GNNQQNY aggregation

2018

Computation

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.

Section: Plummentioning

confidence: 99%

The Role of Conformational Entropy in the Determination of Structural-Kinetic Relationships for Helix-Coil Transitions

Rudzinski

2018

Computation

“…19 The model is transferable in that it aims at describing the essential features of a variety of amino-acid sequences, rather than an accurate reproduction of any specific one. After parametrization, it was demonstrated that the PLUM model folds several helical peptides, 19,[29][30][31][32] stabilizes β-sheet structures, 19,26,[33][34][35] and is useful for probing the conformational variability of intrinsically disordered proteins. 36…”

Section: Plummentioning

confidence: 99%

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

Rudzinski

2017

Preprint

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.

“…Without changing the force-field parameters, the model can also stabilize different helical peptides and assemble β-sheet-rich oligomers. 31 The CG model has been applied to a variety of scenarios involving helical peptides, 34,35 aggregation of β-rich peptides, 36 and β-barrel formation at the interface between virus capsid proteins. 37 The lipid model maps a 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) lipid into 16 beads, using 8 bead types to distinguish different chemical moieties.…”

Section: A Coarse-grained Simulations: Plum Force Fieldmentioning

confidence: 99%

Folding and insertion thermodynamics of the transmembrane WALP peptide

The Journal of Chemical Physics

Bennett

Pfaendtner

et al. 2015

A refined polarizable water model for the coarse-grained MARTINI force field with long-range electrostatic interactions The Journal of Chemical Physics 146, 054501 (2017) The anchor of most integral membrane proteins consists of one or several helices spanning the lipid bilayer. The WALP peptide, GWW(LA) n (L)WWA, is a common model helix to study the fundamentals of protein insertion and folding, as well as helix-helix association in the membrane. Its structural properties have been illuminated in a large number of experimental and simulation studies. In this combined coarse-grained and atomistic simulation study, we probe the thermodynamics of a single WALP peptide, focusing on both the insertion across the water-membrane interface, as well as folding in both water and a membrane. The potential of mean force characterizing the peptide's insertion into the membrane shows qualitatively similar behavior across peptides and three force fields. However, the Martini force field exhibits a pronounced secondary minimum for an adsorbed interfacial state, which may even become the global minimum-in contrast to both atomistic simulations and the alternative PLUM force field. Even though the two coarse-grained models reproduce the free energy of insertion of individual amino acids side chains, they both underestimate its corresponding value for the full peptide (as compared with atomistic simulations), hinting at cooperative physics beyond the residue level. Folding of WALP in the two environments indicates the helix as the most stable structure, though with different relative stabilities and chain-length dependence. C 2015 AIP Publishing LLC. [http://dx