Conformational Analysis of Didemnins. A multidisciplinary approach by means of X-Ray,NMR, molecular-dynamics,and molecular-mechanics techniques

We present the application of several homo- and heteronuclear 1D- and 2D-NMR techniques to assign the ¹H-NMR chemical shifts of the dominant conformation of didemnin B ( 2 ; three different conformations in (D₆)DMSO solution in the ratio 8:1:1) and its conformational analysis, as well as the solution conformation of didemnin A ( 1 ). The conformations were refined by restrained molecular-dynamics calculations using the GROMOS program and by MOMO, a novel personal-computer-based interactive molecular-graphics and molecular-mechanics package, using experimental distances (via a H…H pseudo potential function) as restraints. The solution structures of 1 and 2 obtained by GROMOS and MOMO calculations were compared with each other and related to the recently solved crystal structure of 2 . Focusing on the main conformer, the two kinds of the distance-restrained conformational calculations for 2 yielded a ‘solution structure’ close to the crystal structure. Almost all of the 40 restrained H…H distances coincided (within the estimated standard deviations) with those observed in the crystal structure. One more hydrogen bond was detected in solution involving the lactoyl OH group (disordered in the crystal structure) and the dimethyltyrosine (Me₂Tyr⁵) carbonyl O-atom. The macrocyclic ring system in the modeled solution structure of 1 exhibited a topology close to those of the solution and crystal structures of 2 . The main difference between 1 and 2 could be traced back to a significant change in the Ψ angle of the N-methyl-D-leucine (MeLeu⁷) residue. In 1 , the N-methyl moiety of MeLeu⁷ points inward within the macrocyclic ring toward the 1st and Hip region. We also tested the suitability of structures obtained from NMR data as ‘search fragments’ in the ‘Patterson search approach’ of crystal-structure analysis. It proved possible to resolve the crystal structure of 2 a posteriori with the Patterson search program PATSEE, in this way.