Determination of 3D-Structures of Macromolecules by Restrained Molecular Dynamics on the Basis of Interproton Distances

Abstract

The determination of the 3D-structure of a macromolecule in solution by NMR spectroscopy proceeds in three stages: (i) the sequential assignment of proton resonances, (ii) the determination of a large set of interproton distance restraints, and (iii) the determination of a 3D-structure on the basis of these restraints. Because of the limited range (< 5 A), accuracy and number of the distance restraints that can be determined by NMR using nuclear Overhauser enhancement (NOE) measurements, the task of determining a 3D-structure in solution is far from trivial. Our own approach to this problem has involved the application of restrained molecular dynamics (1–6). This involves the simultaneous solution of the classical equations of motion for all atoms for a suitable time period at an appropriate temperature (7) with the interproton distances incorporated into the total energy function of the system in the form of effective potentials. In this paper we will summarize our results to date using the restrained molecular dynamics approach on oligonucleotides, peptides and proteins.