Protein Designability and Engineering

Rapid scientific and technological advances in biological sciences that started in the second half of the twentieth century have led to exploration and engineering at the scale of single biological molecules. DNA manipulation techniques, such as polymerase chain reaction (PCR), allowed almost arbitrary control of proteins that are expressed in living cells. These developments prompted scientists to ask increasingly ambitious questions pertaining to cell life, evolution, and the molecular origins of diseases. Rational manipulation of protein function throughalteration in sequence and structure becamean important aspect in thequest to answer these questions. A protein’s sequence uniquely defines its three-dimensional structure. This relationship is perhaps themost central paradigm of protein biophysics. Interestingly, however, a protein structure does not uniquely define a single sequence:multiple sequences often correspond to similar protein structures. This aspect turned out to be central for the field of structural bioinformatics. Similarly, a protein’s structure defines its function, although a given structure can have several biological functions. Hence, one approach to manipulate protein function is through its sequence. Nature diversifies protein function through sequence over the course of evolution. This process is often referred to as protein evolution. Understanding protein evolution has become an important subject because of the temptation to manipulate protein function through rational alternation in protein structure via its sequence. This process is referred to as protein design or protein engineering, although the latter term has a grander-scale connotation, best applicable tomore complex systems such as protein–protein or protein–DNA complexes. Howcan themanipulation of protein function help in understanding cellular life and the molecular origins of diseases?Themost obvious applications are direct examinations of how