Water-accessible surface

Protein molecules contain both polar and apolar groups. For proteins dissolved in water, these apolar groups tend to be buried in the interior of the globular structure, as a result of expulsion by the surrounding water. However, other interactions, as well as geometrical constraints, interfere with the hydrophobic effect, so that a minor fraction of the water-accessible surface of the protein molecule may be apolar. Protein molecules that do not spontaneously aggregate in water do not have pronounced apolar patches at their surfaces. 

The authors also computed the polar parts of the van der Waals surface (Eq. 10) and the water-accessible surface (Eq. 11) using a Roche in-house program, MOLOC, and achieved relationships of similar quality to Young s model (Eq. 1) ... 

The introduced cysteine residues are found in one of three possible environments (1) on the water-accessible surface, (2) within the protein interior, or (3) at the protein-lipid interface (Karbn and Akabas, 1998). 

This part of the case study was broken into two sections, the original descriptor set (2,125,127) (Hansch descriptors) and a new set of descriptors calculated in MOE (6) (MOE descriptors). The MOE Descriptors were calculated for molecules assigned Gasteiger (70) partial charges in the MMFF (46-52). The new descriptor set is constructed of three properties. The water accessible surface area (ASA) calculated using a radius of 1.4 A for a water molecule and the... 

Analysis of the Hansch descriptors illustrates that increasing the lipophilicity property for this series of compounds will increase the bioactivity in a more dramatic fashion than increasing the Tafts steric parameter. Increasing the water accessible surface area (MOE descriptor) will increase the bioactivity of the compounds. But there is more than just adding lipophilicity and water accessible surface area to the molecules to increase binding affinity. A comparison of the substituents to the bioactivities illustrates that the bulkier X and Y groups increase bioactivity in conjunction with atomic partial charge distribution of the substituents. 

The C5+, and smeta values were experimentally determined, and the ASA, vdW and logP (o/w) were determined in MOE. [7t = lipophilicity parameter o+ = Hammett constant for ben-zylic cations Esmeta = Tafts steric parameter ASA = water accessible surface area vol = van der Waals volume logP (o/w) = log of the octanol/water partition coefficient.]... 

A modification of the atomic approach was also proposed by Gaillard et al. using molecular lipophilicity potential (MLP) as a 3D source of two lipophilicity parameters calculated from the water-accessible surface, namely a hydrophobic parameter expressed as the sum ofthe positive lipophilicity potential (EM LP+) and a polar parameter expressed as the sum of the negative lipophilicity potential (EMLP—)... 

The understanding gained by the work of Kuzmin and co-workers on ESPT kinetics of naphthols in lipid bilayers has been used by Mishra and co-workers [87-92] for developing a novel steady-state fluorimetric method to study certain membrane properties. It was observed that the two-state distribution (Fig. 1) of INpOH and 2NpOH between the hydrophobic inner site and water-accessible surface site is a sensitive function of the membrane physical state [87],... 

Water accessible surface area Water accessible surface area of all hydrophobic atoms... 

Water accessible surface area of all atoms with negative partial charge Water accessible surface area of all atoms with positive partial charge Total charge of the molecule Number of rotatable single bonds Log of the octanol/water partition coefficient... 

In addition, the results of absorption studies for a series of (i-adrenoceptor blockers in vitro using Caco-2 monolayers and rat intestinal segments have been used to test new descriptors [55]. For this purpose, the authors calculated dynamic molecular surface properties considering all low-energy conformations. Molecular mechanics were used to consider the flexibility of the molecules, and the van der Waals volume (vdW) and water-accessible surface areas were also calculated (Table 4.18 and 4.19). When the dynamic polar vdW surface areas were used in regression analysis to describe cell permeability data obtained in Caco-2 cells and in rat ileum, excellent correlations were obtained (r2 = 0.99 and 0.92 respectively). 

The binding site crevice was probed by cysteine accessibility mapping, where each amino acid from TM6 was replaced by a Cys residue and tested for reactivity to methanethiosulfonate ethylammonium [38]. The comparative study accross mu, delta, and kappa receptors showed a water-accessible surface on the extracellular face of the helix for all opioid receptors and located above the Pro kink (Ile277 and Phe280 to Leu286 in the delta receptor). The data were consistent with the notion of an opioid binding pocket penetrating the upper half of the helical bundle (see Fig. 1A). 

These relationships clearly indicate that the water-accessible surface area per subunit decreases as the protein molecules aggregate to form larger particles. 

Have a higher water-accessible surface area compared with their native counterparts. 

Molecular volume represents the water-excluded volume (in A ), i.e. the volume enclosed by the water-accessible surface computed at a repulsive value of t-0.2kcalmoT. ... 

E.S. Courtenay, M.W. Capp, M.T. Record Jr., Thermodynamics of interactions of urea and guanidinium salts with protein surface relationship between solute effects on protein processes and changes in water-accessible surface saea. Protein Sci. 10 (2001) 2485-2497. 

A FIGURE 1-9 Proteins vary greatly in size, shape, and function. These models of the water-accessible surface of some representative proteins are drawn to a common scale and reveal the numerous projections and crevices on the surface. Each protein has a defined three-dimensional shape (conformation) that is stabilized by numerous chemical interactions discussed in Chapters 2 and 3. The illustrated proteins include enzymes... 

However, none of these three ways of representing protein structure convey much information about the protein surface, which is of interest because it is where other molecules bind to a protein. Computer analysis can identify the surface atoms that are in contact with the watery environment. On this water-accessible surface, regions having a common chemical character (hydrophoblclty or hydrophlllc-Ity) and electrical character (basic or acidic) can be mapped. Such models reveal the topography of the protein surface and the distribution of charge, both Important features of binding sites, as well as clefts in the surface where small molecules often bind (Figure 3-5d). This view represents a protein as it is seen by another molecule. 

Fig. 34.12. CaUx[4]hydroquinone nanotubes structure, longitudinal one-dimensional H-bond relay vi. intertubular tt-tt stacking, the HREM image of a single nanotube, and the water-accessible surface of the tubes. Each tube has four pillar frames of short H-bonds, and the pore size is 8 X 8 A. The unit cell is drawn by the dashed lines. (Reproduced with permission from American Chemical Society [126,127].)...

The following abbreviations are used R2 -coefficient of determination, Ntr and Nte - number of compounds in training set and test set, Rapp -apparent permeability, Pf-cellular permeability, active trp - active transport, PWASA - polar water accessible surface area, PSA - polar surface area,... 

For the purpose of the analysis of the energetics of protein unfolding, the temperature dependence of the thermodynamical parameters of the transfer to water of various low-molecular-weight compounds has been used to estimate hydration effects, applying the group additivity method in conjunction with the determination of water-accessible surface area changes upon unfolding of proteins of... 

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