The present investigation is concerned with the structural and thermodynamic properties of systems comprised of amyloid proteins with the propensity of self-assembly into supramolecular structures. We employ a two-dimensional coarse-grained model reflective of the potentials governing formation of amyloid fibrils with a cross-β structure. In addition to the pairwise Lennard-Jones (LJ) potential representative of non-bonded side-chain interactions, the strength and directionality of short-range backbone hydrogen bonding is expressed within the 2D Mercedes-Benz (MB) framework. A Markov chain Monte Carlo method was employed to sample configurational space in an isothermal-isobaric (NpT) ensemble, from which ensemble averages, radial distribution functions g(r), fluctuation-derived thermodynamic properties (Cp,κT ) and polymorph size distributions were obtained. Following the in-model classification of (proto)fibril polymorphs, we constructed a structural state diagram across parameter space (ρ*,p*,T*). Fibril elongation was studied under equilibrium conditions in the F1 region, characterised by a constant concentration of free monomers in equilibrium with mature fibrils. The thermodynamic quantities ∆Cp = -3,523 ± 0,088, ∆S = 0,815 ± 0,023 and ∆H = 0,723 ± 0,005 were determined for fibril elongation using an isodesmic model of supramolecular polymerisation, in the models’ reduced units. The derived properties were found to be indicative of an enthalpy-dominated cooperative process, counteracting unfavourable entropic effects associated with the loss of effective degrees of freedom in the system. The findings yielded by the coarse-grained model are in line with the empirically reported thermodynamic stability of the cross-β structure under denaturing conditions.
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