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Proteins are the molecular workhorses of biology, responsible for carrying out a tremendous range of essential biochemical functions. The existence of proteins that can perform such diverse tasks is a testament to the power of evolution, and understanding the forces that shape protein evolution has been a long-standing goal of evolutionary biology. More recently, it has also become a subject of interest among bioengineers, who seek to tailor proteins for a variety of medical and industrial applications by mimicking evolution. Although they approach the study of protein evolution from different perspectives and with different ultimate goals, evolutionary biologists and bioengineers are interested in many of the same broad questions.

In examining these questions, we begin by considering the continuing relevance of one of the earliest analyses of protein evolution, performed >40 years ago by the great chemist Linus Pauling and his colleague Emile Zuckerkandl (Zuckerkandl and Pauling, 1965). Working at the time when it was first becoming feasible to obtain amino acid sequences, Pauling and Zuckerkandl assembled the sequences of hemoglobin and myoglobin proteins from a range of species. They compared the sequences with an eye toward determining the molecular changes that accompanied the evolutionary divergence of these species. But although it was already known [in part from Pauling’s earlier work on sickle cell anemia (Pauling et al., 1949; Ingram, 1957)] that even a single mutation could alter hemoglobin’s function, the number of accumulated substitutions seemed more reflective of the amount of elapsed evolutionary time than any measure of functional alteration. Summarizing their research, Pauling and Zuckerkandl (1965) wrote:

Perhaps the most important consideration is the following. There is no reason to expect that the extent of functional change in a polypeptide chain is proportional to the number of amino acid substitutions in the chain. Many such substitutions may lead to relatively little functional change, whereas at other times the replacement of one single amino acid residue by another may lead to a radical functional change. Of course, the two aspects are not unrelated, since the functional effect of a given single substitution will frequently depend on the presence or absence of a number of other substitutions.

This passage highlights 2 key issues that continue to occupy researchers nearly a half-century later. First, natural proteins evolve through a combination of neutral genetic drift and functionally selected substitutions. Although probably every evolutionary biologist would acknowledge the existence of both types of substitutions, their relative prevalence is debated with often startling vehemence (Gillespie, 1984; Blum, 1992). The intractability of this debate is caused in large part by the difficulty

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