The competition between protein folding and aggregation: Off-lattice minimalist model studies

Abstract

Protein aggregation has been associated with a number of human diseases, and is a serious problem in the manufacture of recombinant proteins. Of particular interest to the biotechnology industry is deleterious aggregation that occurs during the refolding of proteins from inclusion bodies. As a complement to experimental efforts, computer simulations of multi-chain systems have emerged as a powerful tool to investigate the competition between folding and aggregation. Here we report results from Langevin dynamics simulations of minimalist model proteins. Order parameters are developed to follow both folding and aggregation. By mapping natural units to real units, the simulations are shown to be carried out under experimentally relevant conditions. Data pertaining to the contacts formed during the association process show that multiple mechanisms for aggregation exist, but certain pathways are statistically preferred. Kinetic data show that there are multiple time scales for aggregation, although most association events take place at times much shorter than those required for folding. Last, we discuss results presented here as a basis for future work aimed at rational design of mutations to reduce aggregation propensity, as well as for development of small-molecular weight refolding enhancers.

Aggregation in Protein-Based Biotherapeutics: Computational Studies and Tools to Identify Aggregation-Prone Regions

“…14,15,[28][29][30][31][32] In an early study, Gupta et al 28 used multiple chain systems constructed from simple two-dimensional (2D) hydrophobic polar (HP) lattice models. 28 Effects of the changes in denaturant and protein concentration were investigated using Monte Carlo (MC) simulations.…”

Self-assembly dynamics for the transition of a globular aggregate to a fibril network of lysozyme proteins via a coarse-grained Monte Carlo simulation

“…Such organized structures are believed to cause a number of neurodegenerative disorders (Alzheimer, Parkinson, Coronary heart, etc.). [1][2][3][4][5][6][7][8][9][10][11][12] Many different human proteins such as beta-amyloid, alpha-synuclein, lysozyme, and insulin, with different sequences and structures can form insoluble amyloid fibrils with somewhat similar morphology. 13 Enormous efforts have been made in attempting to understanding the underlying mechanisms.…”

“…12 Many of the computational investigations have been limited to self-assembly of peptides 14 and short segments of the proteins. [1][2][3][4] The protein dynamics remain an open problem. 15 Enormous computational efforts employing various approaches have been made, involving atomic scale structures to coarse-grained representations, first principle force-fields to phenomenological interactions, structure-based constraints to knowledge-based contacts, etc.…”

“…Investigating the structural transitions with simulations that involve many proteins, solvent, and a host of other constitutive elements is even more challenging. [1][2][3][4][5] In order to study the self-organizing structures involved in fibril formation, aggregation, dispersion, etc. resulting from the cooperative and competing mechanisms, one has to consider many proteins in a matrix.…”

“…16 Several attempts [1][2][3][4] have already been made to study aggregation of proteins without reference to specific proteins via simplified models with relatively small samples. Some of these studies 1,3,4 include 'minimalist' models involving a few short chains, and MD simulations 2 (replica exchange Langevin dynamics) with a coarse-grained representation (e.g. 27 peptides each with 7 residues to study fibrils, β-barrel, and aggregate structures).…”