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Elucidation of the Structural Basis of Protein Kinetic Stability

Co-Investigator: Wilfredo Colón

Associate Professor, Department of Chemistry and Chemical Biology, Rensselaer Polytechnic Institute
By virtue of their unique three-dimensional (3D) structure, proteins are able to carry out a large number of life-sustaining functions. Our ability to exploit these functions for useful applications that could benefit society, such as functional biomaterials, biosensors, drugs, and bioremediation is limited by various factors, including the marginal kinetic stability of proteins. Most proteins are in equilibrium with their unfolded state and transiently populate partially and globally unfolded conformations during physiological conditions. Proteins that are kinetically stable unfold very slowly so that they are virtually trapped in their functional state, and are therefore resistant to degradation and able to maintain activity in the extreme conditions they may encounter in vivo (Fig. 2) (Cunningham, et al. 1999). This is consistent with the observation that thermodynamic stability alone does not fully protect proteins that are susceptible to irreversible denaturation and aggregation arising from partially denatured states that become transiently populated under physiological conditions (Plaza del Pino, et al. 2000). Therefore, the development of a high energy barrier to unfolding may serve to protect susceptible proteins against such harmful conformational “side-effects”. Furthermore, there is compelling evidence suggesting that the deterioration of an energy barrier between native and pathogenic states as a result of mutation, may be a key factor in the misfolding and aggregation of proteins linked to amyloid diseases (Plaza del Pino, et al. 2000; Kelly 1996).

Few proteins in nature are kinetically stable and the structural basis for this property is poorly understood. One of the goals of the Colón Lab is to understand the structural basis of kinetic stability. We are developing a high throughput methods for the identification of kinetically stable proteins that will allow us to build a database of such proteins that have known 3D structure. We will then collaborate with computational biophysisists to elucidate the structural basis of protein kinetic stability. The robustness of the model resulting from computational studies will be determined by testing its ability to predict the kinetic stability of proteins. Our long-term goal is to engineer proteins of importance in biotechnology applications that require the enhanced structural properties of kinetically stable proteins. Another potential application is the collaboration with computational drug-design chemists to guide the design of small molecules for the purpose of endowing proteins with kinetic stability.

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