Proteins flexibility

The problem of protein flexibility can be exemplified with both the families of protein kinases and protein phosphatases. 

Statistics including large and diverse sets of protein structures have revealed that the 20 amino acid residue types exhibit distinctly different levels of flexibility [138], Gin residues appear to be amazingly flexible (given their medium size) and are used in the following section for exemplifying some of the caveats that complicate binding site comparisons. 

---

VS Shenoy, T Ichiye. Influence of protein flexibility on the redox potential of nibredoxm Energy minimization studies. Proteins 17 152-160, 1993. 

Teague S. J. (2003). Implications of protein flexibility for drug discovery. Nature Reviews Drug Discovery 2 527-541. 

However, in most cases enzymes show lower activity in organic media than in water. This behavior has been ascribed to different causes such as diffusional limitations, high saturating substrate concentrations, restricted protein flexibility, low stabilization of the enzyme-substrate intermediate, partial enzyme denaturation by lyophilization that becomes irreversible in anhydrous organic media, and, last but not least, nonoptimal hydration of the biocatalyst [12d]. Numerous methods have been developed to activate enzymes for optimal use in organic media [13]. 

Erickson JA, Jalaie M, Robertson DH, Lewis RA, Vieth M. Lessons in molecn-lar recognition the effects of ligand and protein flexibility on molecular docking accuracy. J Med Chem 2004 47 45-55. 

This extraordinary study shows with great clarity how far we now are from a reliable understanding of either the linkage between protein flexibility and tunneling in the most general sense, or the physical models that underlie anomalous temperature dependences of isotope effects. 

Kohen, A. and Klinman, J.P. (2000). Protein flexibility correlates with degree of hydrogen tunneling in thermophilic and mesophilic alcohol dehydrogenases. J. Am. Chem. Soc. 122, 10738-10739... 

Carlson HA. 2002. Protein flexibility and drug design how to hit a moving target. Curr Opin Chem Biol 6(4) 447-452. 

Jacobs DJ, Rader AJ, Kunh LA, Thorpe MF. 2001. Protein flexibility predictions using graph theory. Proteins 44(2) 150-165. 

Fig. 4. Schematic representation of template-assembled synthetic proteins. The conforma-tionally restricted template can be orthogonally protected and sequentially linked to helical segments to form a large variety of functionalized TASP proteins. Flexible spacers that connect the folded peptide segments and the template provide the necessary conformational freedom that will allow the hydrophobic residues to find their optimum orientations for packing the core...

HMGA proteins flexible players in a structured world... 

Wong, C.F. Mccammon, J.A. Protein flexibility and computer sided drug design. Annu. Rev. Pharmacol. Toxicol. 2003, 43, 31-45. 

Corbeil, C. R., Moitessier, N. (2009) Docking ligands into flexible and solvated macromolecules. 3. Impact of input ligand conformation, protein flexibility, and water molecules on the accuracy of docking programs. J Chem Inf Model 49, 997-1009. 

B-Rao, C., Subramanian, J., Sharma, S. D. (2009) Managing protein flexibility in docking and its applications. Drug Discov Today 14, 394-400. 

Induced fit docking (IFD) should be carried out periodically to check whether inclusion of flexibility of receptor improves docking results or not. Regular docking, while very fast, treats all amino acids rigid which does not reflect the true nature of protein flexibility and consequently true positives may be missed. 

---