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

Abstract

The self-organizing dynamics of lysozymes (an amyloid protein with 148 residues) with different numbers of protein chains, Nc = 1,5,10, and 15 (concentration 0.004 – 0.063) is studied by a coarse-grained Monte Carlo simulation with knowledge-based residue-residue interactions. The dynamics of an isolated lysozyme (Nc = 1) is ultra-slow (quasi-static) at low temperatures and becomes diffusive asymptotically on raising the temperature. In contrast, the presence of interacting proteins leads to concentration induced protein diffusion at low temperatures and concentration-tempering sub-diffusion at high temperatures. Variation of the radius of gyration of the protein with temperature shows a systematic transition from a globular structure (at low T) to a random coil (high T) conformation when the proteins are isolated. The crossover from globular to random coil becomes sharper upon increasing the protein concentration (i.e. with Nc = 5,10), with larger Rg at higher temperatures and concentration; Rg becomes smaller on adding more protein chains (e.g. Nc = 15) a non-monotonic response to protein concentration. Analysis of the structure factor (S(q)) provides an estimate of the effective dimension (D ≥ 3, globular conformation at low temperature, and D ∼ 1.7, random coil, at high temperatures) of the isolated protein. With many interacting proteins, the morphology of the self-assembly varies with scale, i.e. at the low temperature (T = 0.015), D ∼ 2.9 on the scale comparable to the radius of gyration of the protein, and D ∼ 2.3 at the large scale over the entire sample. The global network of fibrils appears at high temperature (T = 0.021) with D ∼ 1.7 (i.e. a random coil morphology at large scale) involving tenuous distribution of micro-globules (at small scales).

Structural variation of alpha-synuclein with temperature by a coarse-grained approach with knowledge-based interactions

“…We hope our findings of the structural response of free ASN to temperature, complement the current simulations, and provide additional tools for the interpretation of the laboratory observations. There are many parameters such as the effects of solvent and the underlying matrix in vivo and in vitro scenarios including protein concentration 61 that we will explore in our future efforts.…”

Self-Organized Morphology and Multiscale Structures of CoVE Proteins

“…A coarse-grained model of a protein is used on a cubic lattice as in our previous studies. [9][10][11] The CoVE protein is a chain consisting of L c = 76 residues 12,17 in a specific sequence. A residue is represented by a cubic node of size (2a) 3 , where a is the lattice constant.…”

“…[4][5][6][7][8] The unique evolution of multiscale structures for the self-assembly of specific proteins is also critical for understanding their unique biological functions. Examples include the collective morphology of nucleosomes with a huge variation in length scales, 9 fibril formation of amyloid in neurodegenerative diseases, 10 the creation of a network of specific pathways for selective transport in ion channels, 11 etc. The specificity of residues, which enables the unique and versatile response of a protein, offers a great opportunity to explore a diverse range of structures emerging from the interplay between residue-residue and segmental interactions as well as thermal noise and entanglement.…”

“…Self-assembly of proteins [1][2][3][4][5][6][7][8][9][10][11] may result in a matrix that can provide mechanical strength. Depending on its specific characteristics, it may add flexibility with a stable dynamical response to the underlying environment such as a membrane.…”

“…This dichotomy between the cooperative and conflicting nature of the collective response of organized assembly of proteins provides enormous opportunities for designing materials with wideranging and specialized characteristics, as mentioned above; For example, the aggregation of proteins triggered by their conformational changes may lead to undesirable structures such as fibrils of amyloid b-proteins, whereas the self-assembly of proteins into a viral capsid is critical for preserving its genome from external factors. 10 . We focus on the effect of temperature on the self-assembly of CoVE proteins, 17 which has not been investigated in depth to the best of the authors' knowledge.…”