Napoleon Tercero and Curtis Meuse

Currently the paradigm in protein science is: protein sequence determines structure, structure determines dynamics and dynamics control function. Both dynamics and extent of conformational fluctuations of proteins about an average conformation are important in their interaction with the local environment and other molecules. For example, the function of transmembrane proteins has been shown to depend on both their average orientation relative to the membrane plane and the extent of fluctuations about said average. Polarized infrared absorption measurements have traditionally been used to determine only the average orientation of transmembrane proteins, segments thereof and model peptides. However, determining the extent of conformational fluctuations, in the form of a distribution of orientations, by polarized infrared absorption has proven difficult due to the limited information that can be obtained from an absorption spectrum. Towards this end, we propose a technique that takes advantage of the statistical inference method termed 'maximum entropy' to combine experimental absorption information obtained from site-specifically labeled amides and construct an orientational distribution in a model-independent manner. If successful, the technique may be extrapolated to other protein systems such as biopharmaceuticals, where it may be possible to relate the extent of conformational fluctuations to protein efficacy and/or stability.