Sketching protein aggregation with a physics-based toy model

Abstract

We explore the applicability of a single-bead coarse-grained molecular model to describe the competition between protein folding and aggregation. We have designed very simple and regular sequences, based on our previous studies on peptide aggregation, that successfully fold into the three main protein structural families (all-α, all-β, and α + β). Thanks to equilibrium computer simulations, we evaluate how temperature and concentration promote aggregation. Aggregates have been obtained for all the amino acid sequences considered, showing that this process is common to all proteins, as previously stated. However, each structural family presents particular characteristics that can be related to its specific balance between hydrogen bond and hydrophobic interactions. The model is very simple and has limitations, yet it is able to reproduce both the cooperative folding of isolated polypeptide chains with regular sequences and the formation of different types of aggregates at high concentrations. © 2013 AIP Publishing LLC. [http://dx

Steric confinement and enhanced local flexibility assist knotting in simple models of protein folding

“…24 Coarse-grained models have a long history in the field of protein folding [32][33][34][35][36][37][38][39][40][41][42][43][44] and, more recently, also in studies of protein aggregation. [45][46][47][48][49][50][51][52] Here we use Monte Carlo simulations of native centric Go ¯models to study the folding process of a protein embedding a trefoil knot. The original goal of this work is to explore the effects of steric confinement in the folding of knotted proteins.…”

How determinant is N-terminal to C-terminal coupling for protein folding?

“…34 Monte Carlo simulations of coarse-grained models have a long history in the folding literature where they have been used to explore many aspects of protein folding, 20,[35][36][37][38][39][40][41][42][43][44][45][46][47] and, more recently, of protein aggregation. [48][49][50][51][52][53][54] A particularly relevant contribution of lattice models was the prediction of the nucleationcondensation mechanism for small, two-state proteins. [55][56][57][58] An important advantage of these models is that their computational feasibility allows accessing very long timescales resulting into accurate measures of thermodynamics and kinetics of folding and aggregation.…”

Knotted proteins: Tie etiquette in structural biology

“…those traditionally used in classical Molecular Dynamics such as the GROMOS or AMBER force fields (42)) because of their lower computational cost, especially when combined with replica-exchange simulations (43) and other sampling protocols (44) designed to accelerate conformational search and relaxation towards equilibrium. Despite their simplicity, SBMs have been successful in the study of protein folding (34,(45)(46)(47) and, more recently, in exploring other phenomena involving proteins such as aggregation (48)(49)(50), protein fold switches (51), and phase separation (52). Clearly, SBMs, and in particular Gō models, will not be able to correctly model misfolding processes leading to compact non-native states and, more generally, regions of the free energy landscape where non-native interactions play an important role (53-55).…”