The study of molecular adaptation has long been fraught with difficult
ies, not the least of which is identifying out of hundreds of amino ac
id replacements those few directly responsible for major adaptations.
Six studies are used to illustrate how phylogenies, site-directed muta
genesis, and a knowledge of protein structure combine to provide much
deeper insights into the adaptive process than has hitherto been possi
ble. Ancient genes can be reconstructed, and the phenotypes can be com
pared to modern proteins. Out of hundreds of amino acid replacements a
ccumulated over billions of years those few responsible for discrimina
ting between alternative substrates are identified. An amino acid repl
acement of modest effect at the molecular level causes a dramatic expa
nsion in an ecological niche. These and other topics are creating the
emerging field of ''paleomolecular biochemistry.''.