Oligomer distribution of the protein alpha-crystallin
The lens of the mammalian eye contains a highly-concentrated solution of proteins from the crystallin family. The phase behavior in this crowded solution is linked to eye diseases such as cataract and presbyopia, so a fundamental understanding of structure, interactions and dynamics is highly desired. Alpha-crystallin is the most abundant protein in the eye lens, and is suggested to have a chaperon-like role for the thermodynamic stabilization of the eye lens fluid. Structurally, alpha-crystallin forms a polydisperse mixture of oligomeric states. The detailed structure of the oligomeric states has been a matter of debate, but recent experimental results from NMR, cryo-EM and mass spectroscopy on structural ensembles and assembly kinetics provide a reasonable picture of the oligomeric assembly process. In particular, the assembly seems to be dominated by compact dimeric and ring-like hexameric precursors, which then assemble into the final hollow oligomer structure. In the proposed work, we aim to establish a coarse-grained representation of alpha-crystallin monomer that captures the essential properties of the assembly process. We will employ a patchy particle model of the monomers, which allows for anisotropic molecular interactions, and Monte Carlo simulation methods to reproduce the distribution of oligomeric states. Varying the parameters and observing the resultant effects on the simulations will provide essential insight into the causal relationships between molecular interactions and observable properties (e.g., the size distribution of the oligomers). This project is part of a larger effort involving experimental, computational, and theoretical components to understand the interactions and dynamics of crystallin proteins in crowded solutions. In this specific context, a better understanding of the assembly of alpha-crystallin is essential to correct for polydispersity effects on dynamics and phase behavior. Beyond the specific research question regarding the eye lens, the desired model may be useful in studying heat-shock proteins and chaperones, as they share their core structural features with alpha-crystallin. A coarse-grained model would allow interactions in protein mixtures to be studied in a very efficient way, and thus open multiple interesting opportunities for computational studies on biomolecular interaction and chaperone function.