This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Understanding the molecular process of protein folding was one of the goals of 20th century science. That it remains so in the 21st is testament to the intractability of the problem, and to the necessity of new approaches. In terms of its impact on human health, particularly with regard to the neurodegenerative diseases that result from protein misfolding, the importance of such understanding cannot be overstated. There is also an urgent need to understand protein folding to gain insight into enzyme function. Successful completion of the proposed research will determine which amino-acid sequences confer optimal folding stability on small globular proteins. All possible sequences will be interrogated using dynamic combinatorial assembly strategies to access the formidable number of molecules necessary. Analysis of the subset of optimally stable sequences will determine whether any robust sequence-stability relationships exist in small globular proteins. Data from the proposed activity will determine which amino acid sequences confer optimal protein folding stability. In addition to its obvious relevance to the medical community, such information will also be valuable to biophysicists and bioinformaticians. The presence or absence of robust sequence-stability relationships will allow a critical re-evaluation of algorithms that seek to predict protein structure from nucleotide sequences.
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