Computer Simulation of Protein Aggregation
Carol K. Hall
Department of Chemical & Biomolecular Engineering
North Carolina State University
Protein aggregation is a cause or associated symptom of a number of
neurodegenerative diseases including Alzheimer's, Parkinson's and
prion disease. It can also interfere with the recovery of recombinant
proteins during processing and can limit the stability of
protein-based drugs during their packaging, shipping, storage and
administration. We are engaged in a computational study aimed at
understanding the basic physical principles that govern the
competition between protein aggregation and protein folding. A novel
off-lattice, intermediate-resolution protein model, PRIME, has been
developed that is simple enough to allow the simulation of
multi-protein systems over relatively long time scales, yet contains
enough genuine protein-like character to mimic real protein dynamics
when used in conjunction with constant-temperature discontinuous
molecular dynamics, a fast alternative to conventional molecular
dynamics. We are using PRIME to investigate the formation and
properties of fibrillar protein aggregates, the structures that have
been implicated in the pathology of many neurodegenerative diseases
including Alzheimer's and Parkinson's diseases. Simulations have
been performed on systems containing 12 to 96 model polyalanine
peptides, each containing 16 residues. Polyalanine was chosen for
study because synthetic polyalanine-based peptides, which form
a-helical structures at low temperatures and low peptide
concentrations, have been found to form b-sheet complexes (fibrils) in
vitro at high temperatures and high peptide concentrations. In our
simulations we find that at a low peptide concentration, a system of
peptides initially in the random coil state forms alpha-helices at low
temperatures and assembles into large beta-sheet structures at high
temperatures. When the concentration is increased at high
temperatures, the system again forms beta-sheets but these assemble
into fibrils as the simulation progresses. The effect of temperature,
peptide concentration and chain length on the kinetics and
thermodynamics of fibril formation is being explored. Movies of the
simulation will be shown.
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