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. We intend to apply and develop an algorithm described in the attached pre-print (Scaling decomposition of protein topological kinetics). The algorithm is an advancement of a simple, fast approach used earlier by a number protein folding groups to estimate the nucleation pathways of small proteins ~100 aa. The scaling result allows us to study the free energy micro-state landscapes of larger proteins (~2-300 aa). The approach is suprisingly accurate in predicting qualitative (topology level) folding pathways and the presence of folding intermediates. However, it fails both qualitatively and quantitatively for a small fraction of proteins due to the over-simplification of topological and energetic constraints. To be useful to an evolutionary biologist, the predictions obtained from this model need to be more consistent and quantitative -- for example, in detecting cooperative folding units, mapping nucleation pathways, and estimating the free energies of intermediates. We expect that the majority of time alloted from this grant will be spent applying the algorithm to proteins whose equilibrium unfolding and refolding pathways are known from experiment (i.e. such as hydrogen exchange). The remainder, and any new requests for time will be used to apply improvements to the method that emerge from the results of these experiments.
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