Ideas for Solving the Rest of the Protein Folding Problem
Lisa Lapidus, Michigan State University

Protein folding, the process by which an amino acid chain finds the stable structure integral to its function, has been a well-defined problem for more than 50 years but a predictive solution has continued to elude us. It is clear that the physical interactions within the chain and with the surrounding water determines which structure has the lowest free energy but neither computation nor experiment can completely describe the path a protein might take to find it, in part because there is a huge range of timescales on which important folding events can occur. Additionally, understanding protein folding in a cell also requires understanding folding while the chain is being synthesized and how folding competes with aggregation, which leads to diseases such as Parkinson’s and Alzheimer’s.

There has undoubtedly been significant progress in understanding protein folding, in large part due to the tremendous advances in protein structure determination, but it is my view that this reliance on beautiful structures has limited our ability to understand how much disorder plays a role in this complex process. I will discuss recent technical progress in experiment and computation to embrace this complexity in both folding and aggregation processes.

Additional reading:

L. J. Lapidus, Exploring the Top of Protein Folding Funnel by Experiment, Current Opinion in Structural Biology. 23, p. 30-35 (2013).

L.J. Lapidus, Understanding Protein Aggregation from the View of Monomer Dynamics, Molecular Biosystems. 9, p. 29-35 (2012).

Background Review Article:
Dill, KA and MacCallum JL, The Protein-Folding Problem, 50 Years On. Science 23 November 2012: Vol. 338 no. 6110 pp. 1042-1046

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