Structural Bioinformatics, 2nd Edition

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PROTEIN DESIGNABILITY AND ENGINEERING

Nikolay V. Dokholyan

INTRODUCTION

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 through alteration in sequence and structure became an important aspect in the quest to answer these questions.

A protein’s sequence uniquely defines its three-dimensional structure. This relationship is perhaps the most 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 ...