A recent analysis of evolutionary rates in >500 globular soluble enzymes revealed pervasive conservation gradients toward catalytic residues. By looking at amino acid preference profiles rather than evolutionary rates in the same data set, we quantified the effects of active sites on site-specific constraints for physicochemical traits. We found that conservation gradients respond to constraints for polarity, hydrophobicity, flexibility, rigidity and structure in ways consistent with fold polarity principles; while sites far from active sites seem to experience no physicochemical constraint, rather being highly variable and favoring amino acids of low metabolic cost. Globally, our results highlight that amino acid variation contains finer information about protein structure than usually regarded in evolutionary models, and that this information is retrievable automatically with simple fits. We propose that analyses of the kind presented here incorporated into models of protein evolution should allow for better description of the physical chemistry that underlies molecular evolution.