Dynamics of Proteins and Macromolecular Assemblies

32nd Steenbock Symposium - May 18, 2006 to May 21, 2006

Proteins self-organize into exquisitely precise structures, but the actual conformation of a protein fluctuates, and almost never coincides exactly with the average structure observed via X-ray crystallography or other methods. Mounting evidence suggests that these induced motions play specific and essential roles in protein function, but the mechanism is rarely clear, owing in part to the difficulty of direct observation of protein motions.  X-ray crystallography reports the magnitude of atomic fluctuations, but the measurements are reliable only for well-ordered regions, where fluctuations are low.  Crystals can be subjected to time-resolved experiments, but the range of applications is limited to reactions that can be triggered by light or trapped by clever manipulations.  NMR spectroscopy is used to probe the dynamics of particular regions of a protein, but has limitations on interpretation depending on whether the dynamics can be defined as slowly or quickly exchanging and the density of through-space couplings. Mass spectrometry coupled with hydrogen/deuterium exchange and proteolysis has been used in some cases to determine changes in the relative solvent accessibility of amide hydrogens.

Computational methods have been utilized for several decades to study the motion of proteins, but traditional all-atom methods alone remain too computationally expensive to tackle functionally interesting long-time dynamics.  Simplified models have been proposed to describe the equilibrium fluctuations near the native state, as opposed to nonequilibrium processes, such as folding or induced-fit relaxation.  Normal mode analysis allows the decomposition of the fluctuations into collective modes with shared frequencies.  Those with the lowest vibrational frequencies are the most global in scope, and presumably the most relevant for function.  Classification of modes can, in fact, be used to describe and predict key conformational changes. Increasingly, computed normal modes of motion in proteins have been found to coincide with experimentally observed changes.  This leads us to the purpose of this symposium, which is to foster interactions that will lead to improved methods of calculating motions and relating them to biological functions.

Molecule graphic