SNIC
SUPR
SNIC SUPR
Oligomer distribution of the protein alpha-crystallin
Dnr:

SNIC 2018/3-312

Type:

SNAC Medium

Principal Investigator:

Peter Schurtenberger

Affiliation:

Lunds universitet

Start Date:

2018-06-15

End Date:

2019-07-01

Primary Classification:

10402: Physical Chemistry

Secondary Classification:

10603: Biophysics

Allocation

Abstract

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 two previous projects SNIC 2017/1-229 and SNIC 2017/1-554, we have established and successfully used a coarse-grained representation of alpha crystallin monomer based on a rigid assembly of spheres with different orientational patches. We have exploited the model in virtual move Monte Carlo simulations, to allow for both structural and kinetic information. We have succesfully performed a search for suitable parameters for the formation of dimers, hexamers and larger oligomers of different sizes. Based on these results, we are proposing to study pathways of oligomer formation in more detail. Varying the parameters and observing the resultant effects on the system 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.