Homology modelling of annexin I: implicit solvation improves side-chain prediction and combination of evaluation criteria allows recognition of different types of conformational error

Annexin I homology models were built from the annexin V crystalstructure. Three methods for side-chain prediction were testedbased on molecular mechanics conformational search, the useof a rotamer database, or a combination of these two methods.We showed that rotamer-based methods were more efficient andthat molecular mechanics energy minimizations, prior to rotamerselection, did not afford clearly improved predictions. Modelsbuilt in vacuo and with an implicit solvation term were comparedwith the annexin I crystal structure which became availableduring the course of this study. The analysis of solvation energies,root mean square deviations, Xi angles and hydrogen bonds showedthat models built with implicit solvation were of better quality.In annexin V, repeat III displays A-B and D-E loop conformationsquite different from other repeats. Since the sequence differencessuggest that repeat III in annexin I might present a conformationsimilar to other repeats, two annexin I models with differentrepeat III conformations were built and compared to determinewhether the correct conformation could have been predicted.We show that using a combination of evaluation criteria, itis possible to discriminate unequivocally between the nativeand the incorrect fold, stressing that only one criterion shouldnot be used to evaluate protein structures.