Proteins conformational flexibility

Alexov EG, Gunner MR (1997) Incorporating protein conformational flexibility into the calculation of pH-dependent protein properties. Biophys J 72 2075-2093. 

Of great interest to the molecular biologist is the relationship of protein form to function. Recent years have shown that although structural information is necessary, some appreciation of the molecular flexibility and dynamics is essential. Classically this information has been derived from the crystallographic atomic thermal parameters and more recently from molecular dynamics simulations (see for example McCammon 1984) which yield independent atomic trajectories. A diaracteristic feature of protein crystals, however, is that their diffraction patterns extend to quite limited resolution even employing SR. This lack of resolution is especially apparent in medium to large proteins where diffraction data may extend to only 2 A or worse, thus limiting any analysis of the protein conformational flexibility from refined atomic thermal parameters. It is precisely these crystals where flexibility is likely to be important in the protein function. 

The docking problem in its full generality is likely to remain an open problem even in the long term. Too many subproblems are still unsolved, the most urgent ones being the accurate prediction of binding affinity and the handling of protein conformational flexibility. 

E. G. Alexov and M. R. Gunnei Biophys.]., 74,2075 (1997). Incorporating Protein Conformational Flexibility into the Calculation of pH-dependent Protein Properties. 

S. Scheiner and C.W. Kem, Theoretical studies of environmental effects on protein conformation Flexibility of the peptide bond, J. Am. Chem. Soc., 99 (1977) 7042. 

Non-harmonic low frequency (tc= 10 -10 s-1) and relatively high anq>litude motions (0.2 A and more) appear at certain critical temperatures, 180 - 210 K, and degree of hydration (10- 30%) depending on protein structure. Protein conformational flexibility in the nanosecond and subnanosecond time scale was revealed in theoretical calculations in experiments on fluorescence quenching of the buried tryptophane residues, spin labelling and on protein NMR. 

While loops lack apparent stmcmral regularity, they exist in a specific conformation stabilized through hydrogen bonding, salt bridges, and hydrophobic interactions with other portions of the protein. However, not all portions of proteins are necessarily ordered. Proteins may contain disordered regions, often at the extreme amino or carboxyl terminal, characterized by high conformational flexibility. In many instances, these disor-... 

Georgescu RE, Alexov EG, Gunner MR (2002) Combining conformational flexibility and continuum electrostatics for calculating pKas in proteins. Biophys J 83 1731—1748. 

You TJ, Bashford D (1995) Conformation and hydrogen ion titration of proteins A continuum electrostatic model with conformational flexibility. Biophys.I 69 1721-1733. 

Folded and unfolded proteins in solution are dense materials characterized in large part by different degrees of conformational flexibility and solvent exposure. Thus, packing is a foundational issue for their solution thermodynamic properties. Although the developments above... 

Wilmann PG, Petersen J, Pettikiriarachchi A, Buckle AM, Smith SC, Olsen S, Perugini MA, Devenish RJ, Prescott M, Rossjohn J (2005) The 2.1 angstrom crystal structure of the far-red fluorescent protein HcRed Inherent conformational flexibility of the chromophore. J Mol Biol 349 223-237... 

L. Zheng and J.D. Brennan, Measurement of intrinsic fluorescence to probe the conformational flexibility and thermodynamic stability of a single tryptophan protein entrapped in a sol-gel derived glass matrix. Analyst 123, 1735-1744 (1998). 

The presence of flexibility and motion in oligosaccharides, as in the case of proteins or nucleic acids, complicates the utilization of dipolar coupling data in structure refinement. Dipolar couplings are averaged because of conformational flexibility, but it is also possible that the various existing conformations orient differently with respect to the magnetic field. 

To test the hypothesis that the conformational flexibility of the thermophilic enzyme is lower at room temperature than at higher temperatures, Kohen and Klinman measured, by FTIR, the time course of H/D exchange of protein N-H sites in deuterium oxide for the thermophilic alcohol dehydrogenase. Their measurements were made at the optimal host-organism temperature of 65 °C and at 25 °C, below the transition temperature. They also included yeast alcohol dehydrogenase at 25 °C, which is the optimal temperature for its own host organism. 

Virtual screening applications based on superposition or docking usually contain difficult-to-solve optimization problems with a mixed combinatorial and numerical flavor. The combinatorial aspect results from discrete models of conformational flexibility and molecular interactions. The numerical aspect results from describing the relative orientation of two objects, either two superimposed molecules or a ligand with respect to a protein in docking calculations. Problems of this kind are in most cases hard to solve optimally with reasonable compute resources. Sometimes, the combinatorial and the numerical part of such a problem can be separated and independently solved. For example, several virtual screening tools enumerate the conformational space of a molecule in order to address a major combinatorial part of the problem independently (see for example [199]). Alternatively, heuristic search techniques are used to tackle the problem as a whole. Some of them will be covered in this section. 

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