Nuclear Magnetic Resonance Approaches to Membrane Protein Structure

Abstract

To understand the functions of membrane proteins requires the same high level of structural analysis that is now almost routinely applied to globular proteins by integrating results from the experimental methods of structural biology such as atomic resolution, x-ray crystallography, and multidimensional solution nuclear magnetic resonance (NMR) spectroscopy with those from molecular dynamics simulations and other calculations. Unfortunately, membrane proteins are problematic for the experimental and theoretical methods of structural biology, largely because these methods were developed with globular proteins in mind; as a result, both the breadth and depth of the structural analysis of membrane proteins lag far behind those of globular proteins. Structure determination by x-ray diffraction requires high-quality single crystals, and proteins associated with membranes are much more resistant to crystallization than water-soluble globular proteins; the multidimensional NMR methods that are so successful in determining the structures of globular proteins in solution are severely limited by the slow reorientation rates of proteins complexed with lipids; and molecular dynamics calculations of proteins were originally used with globular proteins in vacuum—including the effects of both lipid and solvent molecules in these calculations is an even more daunting task than for solvent molecules alone.