Protein Design - Overview

Overview

The number of possible amino acid sequences is enormous, but only a subset of them will fold reliably and quickly to a single native state. Protein design involves identifying novel sequences within this subset, in particular those with a physiologically active native state. Physically, the native state of a protein is the conformational free energy minimum for the chain. Therefore protein design is the search for sequences which have the chosen structure as a free energy minimum. In a sense it is the reverse of structure prediction: in design, a tertiary structure is specified, and a sequence is identified which will fold to it. Hence it is also referred to as inverse folding.

Prion diseases like mad-cow disease illustrate how important it is that designer proteins possess only one stable conformation. In mad-cow disease, there exists a healthy protein with a fatal weakness: there is another conformation that it can "comfortably" take; the abnormally folded shape has very little free energy and is therefore very stable. For reasons that are not yet fully understood, this mis-folded prion protein can catalyze other proteins of its type to also adopt the mis-folded shape, causing a disease-generating cascade of previously functional proteins to quickly mis-fold. They lose the ability to perform their intended function in the new conformation, and have a tendency to form aggregates called plaques. The buildup of these aggregates in the brain leads to progressive neuronal death, and eventually death of the entire organism. It is therefore easy to see the importance both that a designer protein have only one possible stable tertiary structure, and that researchers exercise extreme diligence to ensure that this remains the case in all environments – especially in vivo.

Read more about this topic:  Protein Design

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