Conformational search of cyclic ionophores & characterization of proline helices with constraints by molecular dynamics studies

Abstract

It has been found that valinomycin assumes a variety of conformations depending on the environment. Its ability to selectively complex with K ions and transport them through the membrane is related to its ability to adopt suitable conformations depending on its surroundings. Hence, the conformational space of valinomycin and its Kcomplex was explored by hightemperature MD studies. From the conformational analysis, which was carried out in terms of the components of valinomycin and all possible hydrogen bonds, the following conclusions have emerged:

Hightemperature MD results MD at 900 K for 100 ps, followed by minimization of the structures obtained, revealed a variety of hydrogenbonded conformations. Apart from the wellknown 41 and 51 types of hydrogen bonds, structures with close distances of the type 61 and 71 were also observed. The stability of some of these structures was tested further by simulation at 100 K.

Residue classification and dihedral analysis The residues of valinomycin and enniatinB can be categorized as peptide-ester (PE) and ester-peptide (EP), in addition to L and D residues. Dihedralangle analysis of the structures obtained from hightemperature MD followed by minimization showed that the maps of DHiv and LLac (EP), and DVal and LVal (PE) of valinomycin, as well as LNMeVal (PE) and DHiv (EP) of enniatinB, are similar to those of the corresponding dipeptides. In valinomycin, the values are more localized than the values, and the distribution of points in different regions of the Ramachandran map is slightly influenced by factors such as sidechain nature and neighbouring residues. The observed conformations and most of the hydrogenbonded structures show (, ) values that fall within the wellcharacterized regions of helix and sheet conformations. EnniatinB appears to be less flexible than valinomycin, as indicated by its restricted (, ) accessions.

The high inherent conformational flexibility of valinomycin, and the relatively lower flexibility of the smaller depsipeptide enniatinB, clearly emerge from these studies. Thus, it appears that conformational entropy plays an important role in biological selectivity.