Proteins conformational fluctuations

Astumian RD (2002) Protein conformational fluctuations and free-energy transduction. Appl Phys Mater Sci Process 75 193-206. doi 10.1007/s003390201406... 

H.-X. Zhou and M. Vijayakumar,/. Molec. Biol., 267, 1002 (1997). Modeling of Protein Conformational Fluctuations in pK Predictions. 

Fluorescence correlation spectroscopy (FCS) measures rates of diffusion, chemical reaction, and other dynamic processes of fluorescent molecules. These rates are deduced from measurements of fluorescence fluctuations that arise as molecules with specific fluorescence properties enter or leave an open sample volume by diffusion, by undergoing a chemical reaction, or by other transport or reaction processes. Studies of unfolded proteins benefit from the fact that FCS can provide information about rates of protein conformational change both by a direct readout from conformation-dependent fluorescence changes and by changes in diffusion coefficient. 

It is clear that the wide range of protein phosphorescence lifetimes is due to various specific quenching mechanisms kq) or due to flexibility of the tryptophan site, thereby affecting km. It also follows that phosphorescence will be very sensitive to conformational fluctuations since subtle changes in distance or orientation relative to a specific quenching moiety within the protein will affect the lifetimes dramatically. The phosphorescence emission from protein tryptophan remains relatively unexplored in terms of investigation of dynamic structure-function relationships. 

Currently suggested models for tunneling increasingly invoke protein dynamics . These models envision either a series of conformational fluctuations that lead to a suitable tunnehng configuration ( passive dynamics ) or a more active role... 

Rosenberg, A. and Somogyi, B. (1986) Conformational fluctuations, thermal stability and hydration of proteins, studies by hydrogen exchange kinetics. n Dynamic of Biochemical systems, edited by S. Damjanovich, T.Keleti and L.Tron, pp. 101-112. Amsterdam Elsevier. 

The insertion of a protein within a membrane not only stabilizes the optimal conformation for the enzyme activity, but also limits the possible conformations it may undergo. Thus, assuming a mechanism for the enzymatic activity, where the underlying assumption is that the conformational fluctuation controls the chemical reaction, a decrease in the number of degrees of freedom for the enzyme increases its probability for... 

Biomolecular recognition is mediated by water motions, and the dynamics of associated water directly determine local structural fluctuation of interacting partners [4, 9, 91]. The time scales of these interactions reflect their flexibility and adaptability. For water at protein surfaces, the studies of melittin and other proteins [45, 46] show water motions on tens of picoseconds. For trapped water in protein crevices or cavities, the dynamics becomes much slower and could extend to nanoseconds [40, 71, 92], These rigid water molecules are often hydrogen bonded to interior residues and become part of the structural integrity of many enzymes [92]. Here, we study local water motions in various environments, from a buried crevice to an exposed surface using site-selected tryptophan but with different protein conformations, to understand the correlation between hydration dynamics and conformational transitions and then relate them to biological function. 

Figure 10 The normalized first moments of the photon echo signal of (a) CA-N3, (b) Hb-N3-, and (c) Hb-CO as a function of delay time T. Note the extended time axis of the Hb-CO data. The inhomogeneity decays with time T due to conformational fluctuations of the proteins.

Recent single-molecule experimental studies of proteins provide more detailed views of protein motions, and confirm that a wide variety of timescales is involved in, e.g., catalytic action of enzymes [7,14,15,19,33], Of course, molecular dynamics simulations have been used to probe motions in single proteins for many years, and advances in both theory and computational science have made simulations a powerful approach to building theoretical understanding of protein dynamics [1], The recent introduction of accelerated molecular dynamics methods is helpful in this context [11]. Although detailed dynamical information is sacrificed to the enhanced sampling of conformational space in these methods, which have been shown to access conformational fluctuations that are revealed by nuclear magnetic resonance experiments on the millisecond... 

Recent studies have shown that conformational fluctuations of proteins can be important in structure-based drug discovery as in the discovery of an unexpected cryptic binding site in the HIV integrase enzyme during the course of molecular dynamics studies (Fig. 11.1) [24]. This helped to pave the way for the discovery of the first in a new class of antiviral agents for HIV/AIDS, the compound Isentress (raltegravir), which was licensed by the U.S. Food and Drug Administration in October 2007. A recent review of work in this area has been published by Amaro et al. [2]. 

Figure 11.2 The image in the upper left panel shows a snapshot of several individual protein molecules immobilized in a gel. Each protein undergoes conformational fluctuations that can be monitored by a fluorescent probe. The fluorescent signal from a single protein molecule, as a function of time, is recorded in the time trace shown in the lower left panel. On the right, the experimental situation and the fluorescent time trace are idealized as a two-state conformational transition process as given in Equation (11.5), with A representing the darker state and B representing the brighter state. Image and data in left panel obtained from Lu et al. [133], Reprinted with permission from AAAS.

---