Protein pocket

The latter would normally require a high pH and the contribution of the enzyme is therefore presumed to be the provision of a suitable environment, within the protein pocket, which allows the dissociation of the coordinated H,0 to occur in a medium of pH 7 which would otherwise be much too low. 

In natural systems dimerization reactions are prevented by the location of the haeme group in a sterically protected protein pocket, which prevents another haeme group approaching and attacking the original haeme. Analogously, protonation reactions are limited by the fact that the haeme group lies in a hydrophobic pocket. 

Geometry-based approach from a geometrical point of view, a cavity is a concave empty space that can be described using 2D (surface) or 3D shape descriptors (19-21). We consider three regions in the protein environment the protein bulk, the bulk solvent and the cavity space. The protein bulk is the space filled by the protein atoms. The bulk solvent is the space outside the protein which differentiates from the space inside the protein which defines the cavity where the drug-like molecule is supposed to bind. The identification of protein pockets by numerical methods suppose the capacity to discriminate first the protein bulk from the rest... 

Panjkovich A, Daura X (2010) Assessing the structural conservation of protein pockets to study functional and allosteric sites implications for drug discovery. BMC Struct Biol 10 9-33... 

Liang J, Edelsbrimner H, Woodward C (1998) Anatomy of protein pockets and cavities measmement of binding site geometry and implications for ligand design. Protein Sci 7 1884-1897... 

Fig. 16.6. Objectives of the first round library. The main goal is to explore the protein pocket probed by the right-hand side of Cpd-1 to improve kinase selectivity and further build SAR knowledge. The single aryl-aryl bond was replaced by three bonds containing an amide group with more flexibility. A registered combinatorial synthesis protocol (LJ0194) was used for this library and a 2x44 plate format was planned before the design of the library.

It is clear that the g values are very sensitive to the presence or absence of hydrogen bonding to the quinone oxygens and to the hydrophobicity of the solvent surrounding or the protein pocket. Also the structure of the quinone itself plays a role.140 However, since the 0-tensor reflects only the global properties of the wavefunction it is still difficult to draw far reaching conclusions from this spectroscopic parameter. This situation will hopefully change when more reliable 0-tensor calculations, e.g. for radicals embedded in proteins, become available, e.g. on the QM/MM level. 

The excellent resolution of the 0-tensor components at W band has been used to measure the relaxation properties of QA in the Zn-substituted bRC of R. sphaeroides.m The experiment showed, in contrast to the respective ubiquinone radical in organic solution, an anisotropic relaxation behavior in the pulse high field ESE experiments. From the analysis of the T2 experiments a motional anisotropy of Q% in the protein pocket was deduced with a preferred libration about the C-O symmetry axis. Recently, similar experiments were also performed on Qb- in ZnbRCs. Compared to QA different echo decay time constants were found. A model was proposed in which the relaxation is related to reorientational fluctuations around the quinones specific H-bonds to the protein.142... 

For sufficiently similar models, this algorithm is extremely useful for deriving common-feature pharmacophores. Its use, however, is restricted to the nearly identical binding pockets conformational differences in the two compared protein pockets will lead to useless results. 

Hybrid multiscale models enable us to focus on the relevant part of a system. For example, Leenders et al. studied the proton transfer process in the photoactive yellow protein (Figure 6.3) [9], They used Car-Parrinello molecular dynamics [10], a QM method for dynamics simulations, to describe the chromophore and its hydrogen-bonded network in the protein pocket (middle and right-hand circles). This was combined with a traditional MD force field of 28 600 atoms, simulating the entire protein in water (left-hand circle). 

Fig. 1. New structure of the FeMo-cofactor found by Rees and collaborators in 2002 (5). (Top structure of the cluster Bottom FeMoco and surrounding ligands and amino acids in the protein pocket.)...

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