A STRUCTURE REFINEMENT METHOD BASED ON MOLECULAR-DYNAMICS IN 4 SPATIAL DIMENSIONS

We have developed a method for structure refinement based on molecular dynamics in four spatial dimensions (4D-MD). The method was applied with success to the structure refinement of Cyclosporin A (CPA) and the lac-repressor headpiece (LAC) using atom-atom distance restraints derived from NMR data, two cases where conventional MD refinement methods failed. In the case of CPA we were able to refine seven out of nine substantially different structures, while conventional MD only refines three structures. Previously, it had appeared to be impossible to refine a given LAC structure with conventional MD methods, manual modifications were necessary in order to fulfil all the distance restraints. In this study we show that LAC can be refined without manual interference and using only 5000 steps (10 ps) of 4D-MD. The latter result is particularly interesting because it indicates that this method may be a very useful tool when modelling loops in proteins. © 1993 Academic Press Limited.