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Pure Appl. Chem. 75(7), 927-936, 2003

Pure and Applied Chemistry

Vol. 75, Issue 7

Exploring the entire conformational space of proteins by high-pressure NMR

K. Akasaka

Department of Biotechnological Science, School of Biology-Oriented Science and Technology, Kinki University, Wakayama 649-6493, Japan and Cellular Signaling Laboratory, RIKEN Harima Institute, Hyogo 679-5148, Japan

Abstract: A protein in solution is a thermodynamic entity, spanning, in principle, the entire allowed conformational space from the fully folded N to the fully unfolded U. Although some alternately or partially folded higher-energy conformers may coexist with N and U, they are seldom detected spectroscopically because their populations are usually quite low under physiological conditions. I describe here a new type of experiment, a combination of multidimensional NMR spectroscopy with pressure, that is capable of detecting and analyzing structures and thermodynamic stability of these higher-energy conformers. The idea is based on the finding that under physiological conditions the conformational order of a globular protein normally decreases in parallel with its partial molar volume (negative dV), so that under equilibrium conditions, the population is shifted to a less and-less-ordered conformer with increasing pressure. In principle, with the high space resolution of the multidimensional NMR, the method enables one to explore protein structure and stability in atomic detail in a wide conformational space from N to U with pressure and temperature as variables. The method will provide us with a strong basis for understanding the fundamental phenomena of proteins:function, folding, and aggregation.

*Plenary lecture presented at the 17th IUPAC Conference on Chemical Thermodynamics (ICCT), Rostock, Germany, 28 July - 2 August 2002. Other presentations are published in this issue, pp.859 -936.


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