NMR Restrained Protein Structure Calculations in Implicit Water/Membrane Environments

Abstract

The aqueous and lipid membrane environments that make up the intra- and extra-cellular compartments of biological organisms are critical for supporting the structural and functional integrity of both soluble proteins and membrane proteins. NMR spectroscopy enables characterization of the structures of both types of proteins in their respective, near-native environments. However, most NMR structures are not calculated in physically realistic environments and de novo structure calculations in explicit solvent or explicit lipids are computationally expensive. Traditionally, NMR structures are calculated with a simplified repulsive term to prevent atom clashing. Such treatment accelerates the calculation but sacrifices non-bonded interactions. To facilitate NMR structure calculations in natural environments we are developing a computationally practical implicit solvent and membrane potential for Xplor-NIH. Here we show that this potential affords significant improvements in the conformational quality, accuracy and precision of the calculated structures. Further, it provides correct embedding of membrane proteins in lipid bilayers, as well as physically meaningful insights about residue-residue and protein-membrane interactions. We also describe extensions of the potential to bicelle and micelle sample environments as well as various membrane systems.This research was supported by grants from the National Institutes of Health (GM 110658; GM 100265; EB002031; CA 179087; CA 030199).