A structure-based alignment of Plasmodium DHFR from 350 Bacilli and plasmid DHFR sequences was performed. The degree of conservation or variability was determined at each site in the structure-based alignment. Phylogenic trees were generated and evidence for horizontal gene transfer was identified. Active-site residues appear to be more highly conserved in plasmid DHFR sequences than chromosomal DHFR sequences. With respect to concerted protein motions, there is greater conservation in plasmid versus chromosomal proteins.