Accessibility side chain flexibility

The accessibility component, called , represents the recognition between the specific protein and the ligand when the ligand is positioned in the protein and exposes the atom i to the enzyme anchor point. It depends on the 3D structure, conformation and chirality of the ligand and the 3D structure and side chain flexibility of the enzyme. Thus, the fc) score is proportional to the exposure of the ligand atom i to the anchor point of a specific enzyme. 

There are now a wide range of methods available to detect domains with amphipathic helicial characteristics at the residue level. However, new methods for describing the amphipathic nature of protein segments at the atomic level are still under development. Attempts to incorporate atomic hydrophobicity values (Cornette et ai, 1987 Tanford, 1978) in describing the amphipathic nature of peptides or other molecules have been described (Eisenberg and McLachlan, 1986). In the future, however, side-chain flexibility, effective solvent-accessible surfaces, electrostatics, and molecular dynamics will have to be included to obtain an accurate description of the amphipathic nature of these protein fragments at an atomic level. 

The separation of Hquid crystals as the concentration of ceUulose increases above a critical value (30%) is mosdy because of the higher combinatorial entropy of mixing of the conformationaHy extended ceUulosic chains in the ordered phase. The critical concentration depends on solvent and temperature, and has been estimated from the polymer chain conformation using lattice and virial theories of nematic ordering (102—107). The side-chain substituents govern solubiHty, and if sufficiently bulky and flexible can yield a thermotropic mesophase in an accessible temperature range. AcetoxypropylceUulose [96420-45-8], prepared by acetylating HPC, was the first reported thermotropic ceUulosic (108), and numerous other heavily substituted esters and ethers of hydroxyalkyl ceUuloses also form equUibrium chiral nematic phases, even at ambient temperatures. 

Although cyclization significantly reduces the accessible conformational space, cyclic peptides often maintain considerable flexibility. 36,37 The more the backbone prefers a single conformation, the more the side chains do the same, at least for the %rangle. The preferred backbone conformation is primarily determined by the tendency to minimize the allylic strain, 24,38 as shown in Scheme 2. If possible, the Ca-proton is syn to the carbonyl oxygen of... 

Optimization of these interactions described above through modification of the acyl side chain increased the affinity over lO -fold, from a value > 10 mM (when none of the interactions are satisfied) to a Km value of 120 nM (for Ro-46-7649 9). The stability of the acyl-enzyme complex also increased (Table 1), possibly because tighter binding of the inhibitor decreases the flexibility of the acyl-enzyme complex and thus the rate of occasional access of water to the ester. 

The extended nature of the PPII helix, with the backbone CO and NH groups pointed out from the helical axis into the solvent in a strategic manner, favors interaction with water molecules. Alanine and residues with long, flexible side chains (such as Glu, Lys, Arg, and Gin) seem not to occlude the backbone from water access, or do so to a limited extent, and are therefore favored in this conformation. However, bulky branched or aromatic residues, such as Leu, He, Val, Trp, Phe, Tyr, and Trp, seem to occlude peptide backbone access to solvent (Persikov et al., 2000 Creamer and Campbell, 2002) (Figure 22.4). 

Figure 1 illustrates the side chains of proteins useful for the formation of neoglycoproteins. Among them, the e-amino group of lysyl side chains is the most frequently used for modification of proteins, because the lysyl group is often abundant, and its side chain is flexible and solvent accessible. In the next four sections, we will describe the sugar attachment via these four functional groups. 

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