In the present work, therefore, we combine long-timescale conventional molecular dynamics, enhanced sampling and empirical valence bond (EVB) simulations to present a comprehensive computational study of a number of wild-type and variant forms of SeHisA, MtPriA and TrpF from Thermotoga maritima (TmTrpF). All variants studied in this work, and the corresponding structures used, are summarized in Table . We chose these systems because, in all three cases, there are high-quality structural data in unliganded and ligand-bound forms. For SeHisA, we chose to study the unliganded and substrate (ProFAR) bound forms, as well as key SeHisA variants from ref. that were selected based on their specificity patterns (specialists vs. generalists, Table ). MtPriA and TmTrpF were similarly selected on the basis of high-quality structural data of each enzyme in both unliganded and product (PRFAR) or product analogue (rCdRP) bound forms respectively, as summarized in Table .