Conformational flexibility, biological

GeUiaar D K, G M Verkhivker, P A Rejto, C J Sherman, D B Fogel, L J Fogel and S T Freer 1995 Molecular Recognition of the Inhibitor AG-1343 by HFV-l Protease Conformationally FlexibL Docking by Evolutionary Programming. Chemistry and Biology 2 317-324. 

The spin-spin coupling constants [2-4] of the enkephalins in solution can be interpreted in terms of folded conformations resembling that of morphine in the placement of the residues which appear important for biological activity. X-ray crystallography and theoretical calculations (4-9) have also shown that methionine and leucine enkephalin adopt conformations similar to those concluded from NMR studies. Hence it would appear that opioid peptides can topographically resemble the opiates by assuming preferred, folded, conformations. However, earlier studies from this laboratory (TO) have shown that NMR data can be interpreted in terms of a conformationally flexible structure for methionine enkephalin. 

A considerable body of evidence has appeared which indicates that the receptor site in an enzyme may be located in a very flexible pocket, and that protein molecules in general can show a startlingly large degree of conformational flexibility. This does not affect the nature of steric effects in biological systems. Excluding steric effects in the transport step of bioactivity (2.1) we may divide the steric effect into two components ... 

Novel properties of peptides can be obtained by incorporation of Saa. Peptides are characteristically highly flexible molecules whose 3D structure is strongly influenced by their environment. Their often unordered conformation in solution complicates their use in determining the receptor bound bioactive structure.182,831 Conformational constraints,184-881 cyclization/891 and/or replacement of the peptide backbone or parts of it162 90-921 can provide information on the required conformation for biological activity. 

Some 20 years ago it was observed that certain antibiotics could induce the movement of aqueous K+ ions into the mitochondria of cells, but not that of aqueous Na+ ions. These antibiotics, many of which are naturally occurring, are termed ionophores, i.e. neutral molecules which can mediate the transport of the essential groups IA and IIA cations across biological membranes.76 The essential features of an ionophore are a highly polar interior, a hydrophobic exterior and conformational flexibility. Many are cyclic peptides, the coordination properties of the cyclic molecules are considerably different to those of the linear peptides. These differences are outlined in Chapter 20.2. 

SAR studies on melatonin analogues showed that methoxy and amido moieties are important for binding to melatonin receptors various substituents on the 2nd position of the indole ring enhance the binding affinity [52-54]. The conformational flexibility of the C-3 ethylamido side chain is probably responsible for the broad spectrum of biological activities. As a powerful antioxidant melatonin was shown to have significantly broader actions including oncostatic effects [55], immune system stimulation [56], and antiinflammatory functions [57,58]. 

The fact that receptor binding is a 3-D event would suggest that 3-D descriptors are best able to model biological activity however, there are significant problems inherent in the use of such descriptors. These problems relate to representation of the conformational space available to molecules— for example, the method used to generate the 3-D structures and the way in which conformational flexibility is handled. However, despite these difficulties... 

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