Multiple conformational states

Fiber, R. Karplus, M. Multiple conformational states of proteins a molecular dynamics analysis of myoglobin. Science 235 318-321, 1987. 

Lee B, Sharron M, Blanpain C, et al. Epitope mapping of CCR5 reveals multiple conformational states and distinct but overlapping structures involved in chemokine and coreceptor function. J Biol Chem 1999 274(14) 9617-9626. 

To achieve receptor desensitization and activation by ligand, multiple conformational states of the receptor are required. The binding steps represented in horizontal equilibria are rapid vertical steps reflect the slow, unimolecular isomerizations involved in desensitization (scheme 2). Rapid isomerization to the open channel state (scheme 1) should be added. To accommodate the additional complexities of the observed fast and slow steps of desensitization, additional states have to be included. 

Receptors, like all proteins, are known to spontaneously adopt a variety of conformations, and current concepts of receptor function (e.g., the extended and cubic ternary complex models) are based on the allosteric transitions between multiple conformational states. Some of these conformations are called active because they are able to interact with cellular signal transduction mechanisms (and are the basis of constitutive receptor activity ). If one assumes that different receptor conformations might present different intracellular portions of a... 

Fig. 1. Small peptides can assume multiple conformational states in the solid state. The hydrogen-bonding patterns for two crystalline forms of Met-enkephalin (A and B) and a potent derivative of Met-enkephalin as determined by X-ray crystallography are illustrated (Smith and Griffin, 1978 Stezowski et al., 1985 Griffin et al., 1986). The conformations are antiparallel /3 pleated sheet (A), type I /3 turn (B), and type II j8 turn (C).

Spectroscopic studies have consistently demonstrated the existence of multiple conformational states for the metal sites in transferrins, especially when using metal ions other than Fe3+ and anions other than C032. The differences are not necessarily related to intrinsic geometrical differences between the two sites in each molecule, but also reflect changes dependent on pH, the nature of the synergistic anion, or salt effects. 

Even proteins that contain only a single Trp residue generally exhibit multiexponential decays. Several hypotheses have been proposed to explain why. Pirst, multiple conformational states may exist for the single Trp such as different rotameric configurations (orientations about the Trp xi or X2 C-C bond) (18). Even in the absence of mnltiple rotamers, the electron-transfer qnenching rate is extremely sensitive to the local environment, so a distribntion of local microconformational states may cause a nonexponential flnorescence decay. Other possible sonrces of nonexponential flnorescence decay inclnde the response of the protein and surronnding solvent to the change in dipole moment of Trp on excitation ( solvation ) (19). 

There is a formal similarity between the possibilities of multiple steady states for a biochemical reaction system and of multiple conformational states available to a protein. Ultimately, if concentration constraints are removed from the reaction system, it will relax to equilibrium. Similarly, proteins in nonequilibrium conformational states, i.e., states that do not have the global minimum free energy, will eventually relax to the equilibrium state, although this may take a long time if there are substantial activation energy barriers among the metastable and equilibrium conformational states. 

R. Elber and M. Karpins (1987) Multiple conformational states of proteins A molecular dynamics analysis of Myoglobin. Science 235, pp. 318-321 P. Deuflhard, W. Huisinga, A. Fischer, and C. Schiitte (2000) Identification of almost invariant aggregates in reversible nearly uncoupled Markov chains. Lin. Alg. Appl. 315, pp. 39-59... 

Yuan W, Bazick J, Sodroski J (2006) Characterization of the multiple conformational states of free monomeric and trimeric human immunodeficiency virus envelope glycoproteins after fixation by cross-linker. J Virol 80 6725-6737... 

The first model proposed for the phenomenon of adaptation to constant stimuli, due to Katz Thesleff (1957), sought to explain the desensitization of the acetylcholine receptor following prolonged incubation of the receptor with its ligand. This model was based on the existence of two conformational states of the receptor, one of which is desensitized and possesses a reduced capacity to induce the cellular response. Experimental data confirm the existence of multiple conformational states of the acetylcholine receptor (Changeux, 1981), although these data reveal that the situation is more complex than that considered in the initial model. 

R. Elber and M. Karplus, Science, 235, 318 (1987). Multiple Conformational States of Proteins A Molecular Dynamics Analysis of Myoglobin. 

The CD spectrum of a sample with multiple conformational states is expressed as the Boltzmann population-weighed average of the CD signals of each conformer. 

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