Use of restrained molecular dynamics in water to determine three‐dimensional protein structure: Prediction of the three‐dimensional structure of Ecballium elaterium trypsin inhibitor II

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Abstract
Refinement of distance geometry (DG) structures of EETI-II (Heitz et al.:Biochemistry 28:2392–2398, 1989), a member of the squash family trypsin inhibitor, have been carried out by restrained molecular dynamics (RMD) in water. The resulting models show better side chain apolar/polar surface ratio and estimated solvation free energy than structures refined “in cacuo.” The consistent lower values of residual NMR constraint violations, apolar/polar surface ration and solvation free energy of one of these refined structures allowed prediction of the 3D folding and disulfide connectivity of EETI-II. Except for the few first residues for which no NMR constraints were available, this computer model fully agree with X-ray structures of CMTI-I (Boe et al.: FEBS Lett. 242:285–292, 1989) and EETI-II complexed with trypsin that appeared after the RMD simulation was completed. Restrained molecular dynamics n water is thus proved to highly valuable for refinement of DG structures Also, the successful use of apolar/polar surface ratio and solvation free energy reinforce the analysis of Novotny et al. (Proteins 4: 19–30, 1988) and shows that these criteria are useful indicators of correct versus misfolded models.