(426e) Molecular Simulations of a Biomimetic Polymer in Protein Aggregation

Protein aggregation commonly produces a viscous liquid, which is detrimental for neurological and pharmaceutical considerations. It appears that this universal self-assembly process is rather irreversible, with protein unfolding playing a crucial yet subtle role in this, and therefore, a practical aim is to correspondingly manufacture anti-catalytic agents. In this work via molecular simulations, we consequently examine the kinetic mechanism of a biomimetic polymer:
Although this homopolymer is solely based on a bead-spring model with a square-well potential, it is capable of universally capturing the protein-like unfolding of any heteropolymer [1]. By invoking multiscale strategies, we combine this biomimetic polymer with another convenient model [2], facilitating the examination of protein aggregation throughout its entire phase diagram. Foremost, via the Wang-Landau procedure [3], we calculate the free energy of this self-assembly process, from a pair of polymers to a collection of polymers. In evaluating the kinetic mechanism of protein aggregation, we employ "Transition Path Sampling" with replica exchanges [4], focusing on the corresponding reaction coordinate [5]. We importantly focus on the unfolding of the polymer [6], which in turn appears to be the rate-determining step of the entire process. Our findings consequently have ramifications for the biomedical industry, particularly being relevant for designing anti-catalytic agents that can impede protein unfolding.

[1] M. P. Taylor, W. Paul, and K. Binder. All-or-none protein-like folding transition of a flexible homopolymer chain. Physical Review E 79:050801, 2009.
[2] B. Barz and B. Urbanc. Minimal model of self-assembly: Emergence of diversity and complexity. The Journal of Physical Chemistry B 118:3761–3770, 2014.
[3] F. Wang and D. P. Landau. Efficient, multiple-range random walk algorithm to calculate the density of states. Physical Review Letters 86:2050-2053, 2001.
[4] T. S. van Erp. Reaction rate calculation by parallel path swapping. Physical Review Letters 98:268301, 2007.
[5] B. Peters and B. L. Trout. Obtaining reaction coordinates by likelihood maximization. The Journal of Chemical Physics 125:054108, 2006.
[6] C. Leitold and C. Dellago. Folding mechanism of a polymer chain with short-range attractions. The Journal of Chemical Physics 141:134901, 2014.