Protein aggregation is a serious problem. For example, protein aggregation can interfere with the recovery of recombinant proteins from inclusion bodies, is a cause or associated symptom in diseases such as Alzheimer's disease or Downs syndrome, and can limit the stability of protein-based drugs during their packaging, shipping, storage and administration. An intriguing way to circumvent this problem is to add solutes that have the ability to suppress aggregation, e.g. polyethylene glycol (in vitro) and chaperones (in vivo). This proposal describes a program of theoretical research aimed at understanding the basic principles that underlie protein aggregation, and the mechanisms by which solutes prevent aggregation and enhance refolding. The goal is to develop molecular-level models that capture the essential features that govern the competition between protein refolding and aggregation in both the absence and presence of solutes. By simulating the properties of model proteins and solutes on the computer, we will be able to explore how protein folding and kinetics are influenced by: protein sequence and concentration; denaturant type and concentration; solute type, concentration, and size; and temperature. The proposal has two specific aims: (1) to develop simple, very general, off-lattice protein models based an the heteronuclear square-well chain model and then to use discontinuous molecular dynamics (DMD) to simulate protein folding and aggregation in both the absence and presence of model PEG molecules, and (2) to modify a more realistic protein model, such as one of the more successful intermediate resolution protein folding models, for use with our DMD techniques, thereby enabling efforts to simulate the folding and aggregation of specific small proteins and peptides. These simulations are expected to serve as a future basis for modelling the aggregation of medically important proteins such as beta amyloid, the protein whose aggregation is associated with Alzheimer's disease. Our theoretical work should assist scientists in: (1) choosing and/or designing solutes to suppress unwanted aggregation, (2) optimizing the in vitro refolding of recombinant proteins by manipulation of process variables such as protein concentration, denaturant concentration, etc., and (3) understanding if and how """"""""solutes"""""""" contribute to medically- relevant aggregation such as beta amyloid plaque formation in Alzheimer's disease.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Molecular and Cellular Biophysics Study Section (BBCA)
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Flicker, Paula F
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North Carolina State University Raleigh
Engineering (All Types)
Schools of Engineering
United States
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Wang, Yiming; Shao, Qing; Hall, Carol K (2016) N-terminal Prion Protein Peptides (PrP(120-144)) Form Parallel In-register ?-Sheets via Multiple Nucleation-dependent Pathways. J Biol Chem 291:22093-22105
Curtis, Emily M; Bahrami, Amir H; Weikl, Thomas R et al. (2015) Modeling nanoparticle wrapping or translocation in bilayer membranes. Nanoscale 7:14505-14
Curtis, Emily M; Xiao, Xingqing; Sofou, Stavroula et al. (2015) Phase separation behavior of mixed lipid systems at neutral and low pH: coarse-grained simulations with DMD/LIME. Langmuir 31:1086-94
Latshaw 2nd, David C; Hall, Carol K (2015) Effects of hydrophobic macromolecular crowders on amyloid ? (16-22) aggregation. Biophys J 109:124-34
Cheon, Mookyung; Hall, Carol K; Chang, Iksoo (2015) Structural Conversion of A?17-42 Peptides from Disordered Oligomers to U-Shape Protofilaments via Multiple Kinetic Pathways. PLoS Comput Biol 11:e1004258
Latshaw, David C; Cheon, Mookyung; Hall, Carol K (2014) Effects of macromolecular crowding on amyloid beta (16-22) aggregation using coarse-grained simulations. J Phys Chem B 118:13513-26
Wagoner, Victoria A; Cheon, Mookyung; Chang, Iksoo et al. (2014) Impact of sequence on the molecular assembly of short amyloid peptides. Proteins 82:1469-83
Curtis, Emily M; Hall, Carol K (2013) Molecular dynamics simulations of DPPC bilayers using ""LIME"", a new coarse-grained model. J Phys Chem B 117:5019-30
Wagoner, Victoria A; Cheon, Mookyung; Chang, Iksoo et al. (2012) Fibrillization propensity for short designed hexapeptides predicted by computer simulation. J Mol Biol 416:598-609
Phelps, Erin M; Hall, Carol K (2012) Structural transitions and oligomerization along polyalanine fibril formation pathways from computer simulations. Proteins 80:1582-97

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