The eye lens is composed of bundled fiber cells containing structural proteins, called, crystallins, at concentration exceeding 300 mg/mL. The short-range order and stability in crystallin solutions are responsible for transparency and refractive properties required for proper lens functioning. Over time, high molecular weight crystallin aggregates accumulate in the lens, forming cataracts that render the lens opaque. There exist a number of known point mutations that are associated with hereditary congenital cataract formation. To model protein behavior, we employed fully atomistic Molecular Dynamics simulations. The results of these simulations were used to create a library of protein conformations as an input for the multi-conformational Monte Carlo method developed in our group. This method allows us to model protein-protein interactions and the early stages of protein aggregation in γD- and γS-crystallin solutions at high protein concentrations (over 192 mg/mL) and various values of ionic strength. By comparing simulations of wild-type γ-crystallins and their cataract-related variants, we have gained insight into how point mutations affect protein-protein interactions and large-scale cluster formation. In our simulations the proteins are atomistically detailed and are made flexible by introducing an additional Monte Carlo step that swaps the input conformations with a weighted probability.

Modeling interprotein interactions in concentrated solutions of wild-type and cataract-related variants of γD- and γS-crystallins

251st National Meeting (2016)

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