Development of Multiple Conformation Monte Carlo Method and Its Application to Protein Aggregation in Cataract Formatio

Realistic biological conditions are characterized by high concentrations of biomolecular solutes. Protein conformations and protein-protein interactions can be affected by crowding. The inclusion of a high number of proteins to model such environments necessitates the use of computationally inexpensive methods, such as rigid-body Brownian dynamics or Monte Carlo (MC) simulations. However, the rigid body representation of many protein systems gives rise to artifacts in protein-protein interactions. Presented here is the multi-conformational Monte Carlo (mcMC) method that avoids such artifacts by incorporating molecular flexibility at a low computational cost. We employ it to study the interaction of eye lens proteins, crystallins. In a healthy eye lens crystallins are the structure proteins. Their solubility at concentrations exceeding 400 mg/mL ensures lens transparency. The aggregation of crystallins leads to lens opacification, called cataract. We study how known point mutations associated with cataract formation lead to altered protein-protein interaction and creation of large aggregates.