The ability of proteins to fold into their native state is essential for cell function; misfolded proteins not only lose their function, but can also cause neurodegenerative diseases, including Alzheimer and Huntington. Study of protein folding can aid in preventing protein misfolding diseases and in designing proteins with novel functions. Although most cellular proteins fold on timescales of milliseconds to seconds, several small proteins have been designed and characterized experimentally to fold on a timescale of less than 20 µs. The project will employ Center-developed long-time MD simulation with NAMD to investigate: (1) the folding pathway of λ-repressor and (2) the effect of mutations on folding of the λ-repressor.

Spotlight: Protein Hairpin and Parkinson's Disease (Jan 2016)


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For centuries, millions of people around the globe have been troubled with a movement disorder that usually starts with a tremor in one hand. The disorder, later known as Parkinson's disease, affects commonly older individuals and disrupts patient's movement, sleep and speech from the brain. There is currently no cure for the disease. Key to the disease, progressively occurring in patient's brain, is the loss of neuron cells due to aggregation of a small protein named α-synuclein. Extensive studies have been carried out, yet the function of the protein remains a mystery. It is amazing that aggregation of such small proteins eventually leads to neuronal cell death and generates tremendous difficulties in peoples' life. In a recent report, a team of computational scientists attributed the cause of α-synuclein aggregation to a hairpin structure involving just a small region (amino acids 38-53) in the middle of the protein. With extensive simulations (over 180 μs in total), the researchers revealed that a short fragment encompassing region 38-53, exhibiting a high probability of forming a β-hairpin structure, is a key region during α-synuclein aggregation. Moreover, the researchers predicted a mutation that impedes β-hairpin formation, thereby retarding α-synuclein aggregation. The discoveries, made possible through the software NAMD and VMD, are expected to shed light on the mechanism underlying Parkinson's disease and to inspire the design of drugs. More on our α-synuclein website.

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  • Disulfide bridges: bringing together frustrated structure in a bioactive peptide. Yi Zhang, Klaus Schulten, Martin Gruebele, Paramjit S. Bansal, David Wilson, and Norelle L. Daly. Biophysical Journal, 110:1744-1752, 2016.
  • Transient b-hairpin formation in a-synuclein monomer revealed by coarse-grained molecular dynamics simulation. Hang Yu, Wei Han, Wen Ma, and Klaus Schulten. Journal of Chemical Physics, 143:243142, 2015.
  • Comparing fast pressure jump and temperature jump protein folding experiments and simulations. Anna Jean Wirth, Yanxin Liu, Maxim B. Prigozhin, Klaus Schulten, and Martin Gruebele. Journal of the American Chemical Society, 137:7152-7159, 2015.
  • Observation of complete pressure-jump protein refolding in molecular dynamics simulation and experiment. Yanxin Liu, Maxim B. Prigozhin, Klaus Schulten, and Martin Gruebele. Journal of the American Chemical Society, 136:4265-4272, 2014.
  • Characterization of folding mechanisms of Trp-cage and WW-domain by network analysis of simulations with a hybrid-resolution model. Wei Han and Klaus Schulten. Journal of Physical Chemistry B, 117:13367-13377, 2013.
  • Misplaced helix slows down ultrafast pressure-jump protein folding. Maxim B. Prigozhin, Yanxin Liu, Anna Jean Wirth, Shobhna Kapoor, Roland Winter, Klaus Schulten, and Martin Gruebele. Proceedings of the National Academy of Sciences, USA, 110:8087-8092, 2013.
  • Structural characterization of l-repressor folding from all-atom molecular dynamics simulations. Yanxin Liu, Johan Strümpfer, Peter L. Freddolino, Martin Gruebele, and Klaus Schulten. Journal of Physical Chemistry Letters, 3:1117-1123, 2012.
  • Challenges in protein folding simulations. Peter L. Freddolino, Christopher B. Harrison, Yanxin Liu, and Klaus Schulten. Nature Physics, 6:751-758, 2010.
  • Going beyond clustering in MD trajectory analysis: an application to villin headpiece folding. Aruna Rajan, Peter L. Freddolino, and Klaus Schulten. PLoS One, 5:e9890, 2010. (12 pages).
  • Common structural transitions in explicit-solvent simulations of villin headpiece folding. Peter L. Freddolino and Klaus Schulten. Biophysical Journal, 97:2338-2347, 2009.
  • Force field bias in protein folding simulations. Peter L. Freddolino, Sanghyun Park, Benoit Roux, and Klaus Schulten. Biophysical Journal, 96:3772-3780, 2009.
  • Ten-microsecond molecular dynamics simulation of a fast-folding WW domain. Peter L. Freddolino, Feng Liu, Martin Gruebele, and Klaus Schulten. Biophysical Journal, 94:L75-L77, 2008.
  • Funded by a grant from
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    General Medical Sciences
    of the National Institutes
    of Health