CHEMICAL AND BIOLOGICAL ENGINEERING
WELCOMES
Carol Hall
North
Carolina State University
Hill Conference Room
April 12
11:00
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.