Retention of required structural and functional properties of proteins in species adapted to different temperatures and pressures is achieved through variation in amino acid sequence and accumulation of small organic solutes that stabilize protein traits. Conservation of ligand binding and catalytic rate can be achieved by minor differences in sequence. For orthologs of lactate dehydrogenase-A (A(4)-LDH) temperature adaptation may involve only a single amino acid substitution. Adaptation involves changes in conformational mobility of regions of A(4)-LDH that undergo movement during ligand binding, movements that are rate-limiting to catalysis. A model that integrates adaptations in sequence and intracellular milieu is developed on the basis of conformational microstates. Although orthologs of different thermally adapted species vary in stability, at physiological temperatures it is hypothesized that a similar ensemble of conformational microstates exists for all orthologs. Organic solutes stabilize this ensemble of microstates. Differences among orthologs in responses to organic solutes at a common temperature lead to similar responses at normal body temperatures. Because protein stability increases at high protein concentrations, intrinsic stabilities of proteins may reflect the protein concentrations of the cellular compartments in which they occur. Protein-stabilizing solutes like trimethylamine-N-oxide (TMAO) conserve protein function and structure at elevated hydrostatic pressures.