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Results for “Solvent accessibility”

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PubMed1998

Easy method to predict solvent accessibility from multiple protein sequence alignments.

An easy and uncomplicated method to predict the solvent accessibility state of a site in a multiple protein sequence alignment is described. The approach is based on amino acid exchange and compositional preference matrices for each of three accessibility states: buried, exposed, and intermediate. Calculations utilized a modified version of the 3D_ali databank, a collection of multiple sequence alignments anchored through protein tertiary structural superpositions. The technique achieves the same accuracy as much more complex methods and thus provides such advantages as computational affordability, facile updating, and easily understood residue substitution patterns useful to biochemists involved in protein engineering, design, and structural prediction. The program is available from the authors; and, due to its simplicity, the algorithm can be readily implemented on any system. For a given alignment site, a hand calculation can yield a comparative prediction.

Amino Acid Sequence↗

PubMed1984

Determination of the solvent accessibility of specific aromatic residues in gamma-crystallin by photo-CIDNP NMR measurements.

The surface or solvent accessibility of certain individual aromatic residues of calf-gamma II crystallin in solution (1 mM) were measured by the dramatic intensity enhancements of NMR lines generated by the interactions of cyclic radical pair formation of the 3-N-carboxymethyl lumiflavin (flavin I) dye excited (488nm) by an argon laser (5 watts) with the protein. This effect is called photo-chemically induced dynamic nuclear polarization: photo-CIDNP. The "light" and "dark" NMR spectra were taken in alternating scans in the pulsed Fourier transform mode on a Bruker 360 MHz instrument. Subtraction results in the photo-CIDNP difference spectrum containing lines of the polarized residues. With flavin dyes only tyrosine, histidine, and tryptophan can be polarized. The respective theoretical static accessibility of these residues based upon van der Waal's contact radii have been calculated from the atomic coordinates and provide a basis for evaluating the dynamic NMR photo-CIDNP results and for assigning the resonances. These results suggest that while the four tryptophan residues are completely buried, His-113 and His-14 of the five histidines; and Tyr-165 and Tyr-62 of the fifteen tyrosines are sufficiently exposed to elicit a photo-CIDNP effect. These results confirm and extend the observations previously obtained with theoretical electrostatic programs and FT-NMR measurements.

Animals↗

PubMed2003

POPS: A fast algorithm for solvent accessible surface areas at atomic and residue level.

POPS (Parameter OPtimsed Surfaces) is a new method to calculate solvent accessible surface areas, which is based on an empirically parameterisable analytical formula and fast to compute. Atomic and residue areas (the latter represented by a single sphere centered on the C(alpha) atom of amino acids and at the P atom of nucleotides) have been optimised versus accurate all-atom methods. The parameterisation has been derived from a selected dataset of proteins and nucleic acids of different sizes and topologies. The residue based approach POPS-R, has been devised as a useful tool for the analysis of large macromolecular assemblies like the ribosome and it is specially suited for the refinement of low resolution structures. POPS-R also allows for estimates of the loss of free energy of solvation upon complex formation, which should be particularly useful for the design of new protein-protein and protein-nucleic acid complexes. The program POPS is available at http://mathbio.nimr.mrc.ac.uk/~ffranca/POPS and at the mirror site http://www.cs.vu.nl/~ibivu/programs/popswww.

Algorithms↗

PubMed2006

Predicting the solvent accessibility of transmembrane residues from protein sequence.

In this study, we propose a novel method to predict the solvent accessible surface areas of transmembrane residues. For both transmembrane alpha-helix and beta-barrel residues, the correlation coefficients between the predicted and observed accessible surface areas are around 0.65. On the basis of predicted accessible surface areas, residues exposed to the lipid environment or buried inside a protein can be identified by using certain cutoff thresholds. We have extensively examined our approach based on different definitions of accessible surface areas and a variety of sets of control parameters. Given that experimentally determining the structures of membrane proteins is very difficult and membrane proteins are actually abundant in nature, our approach is useful for theoretically modeling membrane protein tertiary structures, particularly for modeling the assembly of transmembrane domains. This approach can be used to annotate the membrane proteins in proteomes to provide extra structural and functional information.

Cell Membrane↗

PubMed2004

Toward multiplexing the application of solvent accessibility probes for the investigation of RNA three-dimensional structures by electrospray ionization-Fourier transform mass spectrometry.

Multiple solvent accessibility probes can be applied simultaneously to investigate the three-dimensional structure of complex RNA substrates when electrospray ionization-Fourier transform mass spectrometry (ESI-FTMS) is employed in place of polyacrylamide gel electrophoresis (PAGE). We show that classic chemical probes, such as dimethylsulfate, kethoxal, and 1-cyclohexyl-3-(2-morpholinoethyl)carbodiimide metho-p-toluenesulfonate, can be combined in probing mixtures designed to assess the full spectrum of base pairing and steric protection for the most abundant ribonucleotides included in RNA. After probe-independent hydrolysis of the alkylated substrate, the mixture of oligonucleotide products is mass mapped by ESI-FTMS analysis, which enables the unambiguous identification of probed bases from the unique mass signatures provided by the different chemical modifiers. In this bottom-up approach, any theoretical limit to the size of the possible target RNA will be determined by the effectiveness of the hydrolysis procedure rather than by the performance of the detection technique. Control experiments performed on the stem-loop 4 of human immunodeficiency virus type 1 have shown no adverse interactions between the reagents combined in the probing cocktails. No significant discrepancies between the alkylation patterns offered by the cocktails and the individual reagents could be detected, indicating that multiplexing the probe application does not necessarily lead to structural distortion but provides valid data on base accessibility and protection. To demonstrate the ruggedness of this approach, optimized cocktails were finally employed to assess the stability of the folded structure of mouse mammary tumor virus pseudoknot in the presence of different amounts of Mg2+. Multiplexing the probe application constitutes an essential step toward high-throughput applications, which will take advantage of a strategy that maximizes the information attainable from a single experiment, while minimizing time and sample consumption over PAGE-based methods.

Base Sequence↗

PubMed1994

Use of amino acid environment-dependent substitution tables and conformational propensities in structure prediction from aligned sequences of homologous proteins. I. Solvent accessibility classes.

Buried and exposed residues are predicted by composing amino acid substitution patterns and mean propensities for the two solvent accessibility classes with the amino acid residues at equivalent sites in aligned sequences of homologous proteins. In a study of 13 protein families, the accuracy of the prediction is around 77% (the correlation coefficient between the predicted and observed accessibility classes is 0.52). The environment dependent amino acid substitution tables are especially important in prediction of buried hydrophilic and exposed hydrophobic residues, which are not well predicted with propensities alone. Since the prediction is site-specific in the sense that any averaged properties over neighbouring residues are not required, the results can be used for the prediction of secondary structures by detecting periodicity in the sequence of buried and exposed classes.

Amino Acid Sequence↗

PubMed1996

Predicting solvent accessibility: higher accuracy using Bayesian statistics and optimized residue substitution classes.

We introduce a novel Bayesian probabilistic method for predicting the solvent accessibilities of amino acid residues in globular proteins. Using single sequence data, this method achieves prediction accuracies higher than previously published methods. Substantially improved predictions-comparable to the highest accuracies reported in the literature to date-are obtained by representing alignments of the example proteins and their homologs as strings of residue substitution classes, depending on the side chain types observed at each alignment position. These results demonstrate the applicability of this relatively simple Bayesian approach to structure prediction and illustrate the utility of the classification methodology previously developed to extract information from aligned sets of structurally related proteins.

Amino Acid Sequence↗

PubMed2004

An extended aqueous solvation model based on atom-weighted solvent accessible surface areas: SAWSA v2.0 model.

A new method is proposed for calculating aqueous solvation free energy based on atom-weighted solvent accessible surface areas. The method, SAWSA v2.0, gives the aqueous solvation free energy by summing the contributions of component atoms and a correction factor. We applied two different sets of atom typing rules and fitting processes for small organic molecules and proteins, respectively. For small organic molecules, the model classified the atoms in organic molecules into 65 basic types and additionally. For small organic molecules we proposed a correction factor of "hydrophobic carbon" to account for the aggregation of hydrocarbons and compounds with long hydrophobic aliphatic chains. The contributions for each atom type and correction factor were derived by multivariate regression analysis of 379 neutral molecules and 39 ions with known experimental aqueous solvation free energies. Based on the new atom typing rules, the correlation coefficient (r) for fitting the whole neutral organic molecules is 0.984, and the absolute mean error is 0.40 kcal mol(-1), which is much better than those of the model proposed by Wang et al. and the SAWSA model previously proposed by us. Furthermore, the SAWSA v2.0 model was compared with the simple atom-additive model based on the number of atom types (NA). The calculated results show that for small organic molecules, the predictions from the SAWSA v2.0 model are slightly better than those from the atom-additive model based on NA. However, for macromolecules such as proteins, due to the connection between their molecular conformation and their molecular surface area, the atom-additive model based on the number of atom types has little predictive power. In order to investigate the predictive power of our model, a systematic comparison was performed on seven solvation models including SAWSA v2.0, GB/SA_1, GB/SA_2, PB/SA_1, PB/SA_2, AM1/SM5.2R and SM5.0R. The results showed that for organic molecules the SAWSA v2.0 model is better than the other six solvation models. For proteins, the model classified the atoms into 20 basic types and the predicted aqueous free energies of solvation by PB/SA were used for fitting. The solvation model based on the new parameters was employed to predict the solvation free energies of 38 proteins. The predicted values from our model were in good agreement with those from the PB/SA model and were much better than those given by the other four models developed for proteins.

Chemistry, Organic↗

PubMed2006

[Prediction of protein solvent accessibility with Markov chain model].

Residues in protein sequences can be classified into two (exposed / buried) or three (exposed/intermediate/buried) states according to their relative solvent accessibility. Markov chain model (MCM) had been adopted for statistical modeling and prediction. Different orders of MCM and classification thresholds were explored to find the best parameters. Prediction results for two different data sets and different cut-off thresholds were evaluated and compared with some existing methods, such as neural network, information theory and support vector machine. The best prediction accuracies achieved by the MCM method were 78.9% for the two-state prediction problem and 67.7% for the three-state prediction problem, respectively. A comprehensive comparison for all these results shows that the prediction accuracy and the correlative coefficient of the MCM method are better than or comparable to those obtained by the other prediction methods. At the same time, the advantage of this method is the lower computation complexity and better time-consuming performance.

Algorithms↗

PubMed1994

[Determination of solvent accessibility of residues of aromatic amino acids in proteins using the second derivative of the UV-absorption spectrum].

A new method for determining the solvent accessibility of tyrosine and tryptophan residues in proteins from the wavelengths of absorption peak maxima in secondary derivatives of UV absorption spectra has been developed. Analytical expressions for calculating the number of groups in latent and exposed states of amino acid residues in protein globules were obtained on the basis of the previously elaborated mathematical model of spectral changes observed during the transition between those respective states. The new procedure was used to analyze sixteen proteins and showed a good correlation between the experimental results and literary data.

Models, Theoretical↗

PubMed1999

Approximate solvent-accessible surface areas from tetrahedrally directed neighbor densities.

A fast analytical formula (TDND) has been derived for the calculation of approximate atomic and molecular solvent-accessible surface areas (SASA), as well as the first and second derivatives of these quantities with respect to atomic coordinates. Extending the work of Stouten et al. (Molecular Simulation, 1993, Vol. 10, pp. 97-120), as well as our own (Journal of Computational Chemistry, 1999, Vol. 20, pp. 586-596), the method makes use of a Gaussian function to calculate the neighbor density in four tetrahedral directions in three-dimensional space, sometimes twice with different orientations. SASA and first derivatives of the 2366 heavy atoms of penicillopepsin are computed in 0.13 s on an SGI R10000/194 MHz processor. When second derivatives are computed as well, the total time is 0.23 s. This is considerably faster than timings reported previously for other algorithms. Based on a parameterization set of nineteen compounds of different size (11-4346 atoms) and class (organics, proteins, DNA, and various complexes) consisting of a total 23,197 atoms, the method exhibits relative errors in the range 0.2-12.6% for total molecular surface areas and average absolute atomic surface area deviations in the range 1.7 to 3.6 A(2).

Molecular Structure↗

PubMed2001

Predicting octanol/water partition coefficient using solvation free energy and solvent-accessible surface area.

The regression model for octanol/water partition coefficients (Kow), is founded with only two molecular descriptors available through quantum chemical calculations: solvation free energy (delta Gs), and solvent-accessible surface area (SASA). For the properties of 47 organic compounds from 17 types, the model gives a correction coefficient (adjusted for degrees of freedom) of 0.959 and a standard error of 0.277 log unit. It is a suitable way to predict the partition properties that are related to solute-solvent interactions in the water phase.

Kinetics↗

PubMed1984

Solvent accessible surface area and excluded volume in proteins. Analytical equations for overlapping spheres and implications for the hydrophobic effect.

An analytical formula has been derived for the calculation of the solvent accessible surface area of a protein molecule or equivalently the surface area exterior to an arbitrary number of overlapping spheres. The directional derivative of this function with respect to atomic co-ordinates is provided to facilitate minimization procedures used with molecular docking algorithms and energy calculations. An analytical formula for the calculation of the volume enclosed within the accessible surface, the excluded volume, is also derived. Although the area function is not specific to the structures of proteins, the derivation was motivated by the need for a computationally feasible simulation of the hydrophobic effect in proteins. A computer program using the equations for area has been tested and has had limited application to the docking of protein alpha-helices. Possible relationships of the solvent excluded volume to hydrophobic interaction free energy and transfer free energy of solute molecules are derived from the statistical mechanics of solution.

Mathematics↗

PubMed2003

Relationship between intramolecular hydrogen bonding and solvent accessibility of side-chain donors and acceptors in proteins.

This study shows that intramolecular hydrogen bonding in proteins depends on the accessibility of donors and acceptors to water molecules. The frequency of occurrence of H-bonded side chains in proteins is inversely proportional to the solvent accessibility of their donors and acceptors. Estimates of the notional free energy of hydrogen bonding suggest that intramolecular hydrogen-bonding interactions of buried and half-buried donors and acceptors can contribute favorably to the stability of a protein, whereas those of solvent-exposed polar atoms become less favorable or unfavorable.

Amino Acids↗

PubMed2004

Accurate and efficient generalized born model based on solvent accessibility: derivation and application for LogP octanol/water prediction and flexible peptide docking.

A novel method for fast and accurate evaluation of the generalized Born radii in macromolecular solvation electrostatics calculations is proposed, based on the solvent accessibility of the first two solvation layers around an atom. The reverse generalized Born radii calculated by the method have correlation coefficient of 98.7% and RMSD of 0.031 A(-1) with the values obtained using a precise but significantly slower numerical boundary element solution. The method is applied to derive an estimate of the free solvation energy difference between octanol and water and to predict LogP octanol-water. A nine-parameter model is optimized on an 81 compound training set and applied to predict LogP(ow) for an external evaluation set of 19 drug molecules with RMSD of 0.9. The new GB approximation is also tested in Monte Carlo docking simulations of the fully flexible p53 peptide fragment to MDM2. The best energy solution found in the simulations has RMSD of 2.8 A to the X-ray structure.

Algorithms↗

PubMed2004

Solvent accessibility in native and isolated domain environments: general features and implications to interface predictability.

A non-redundant database of 4536 structural domains, comprising more than 790,000 residues, has been used for the calculation of their solvent accessibility in the native protein environment and then in the isolated domain environment. Nearly 140,000 (18%) residues showed a change in accessible surface area in the above two conditions. General features of this change under these two circumstances have been pointed out. Propensities of these interfacing amino acid residues have been calculated and their variation for different secondary structure types has been analyzed. Actual amount of surface area lost by different secondary structures is higher in the case of helix and strands compared to coil and other conformations. Overall change in surface area in hydrophobic and uncharged residues is higher than that in charged residues. An attempt has been made to know the predictability of interface residues from sequence environments. This analysis and prediction results have significant implications towards determining interacting residues in proteins and for the prediction of protein-protein, protein-ligand, protein-DNA and similar interactions.

Amino Acids↗

PubMed2004

Importance of solvent accessibility and contact surfaces in modeling side-chain conformations in proteins.

Contact surface area and chemical properties of atoms are used to concurrently predict conformations of multiple amino acid side chains on a fixed protein backbone. The combination of surface complementarity and solvent-accessible surface accounts for van der Waals forces and solvation free energy. The scoring function is particularly suitable for modeling partially buried side chains. Both iterative and stochastic searching approaches are used. Our programs (Sccomp-I and Sccomp-S), with relatively fast execution times, correctly predict chi1 angles for 92-93% of buried residues and 82-84% for all residues, with an RMSD of approximately 1.7 A for side chain heavy atoms. We find that the differential between the atomic solvation parameters and the contact surface parameters (including those between noncomplementary atoms) is positive; i.e., most protein atoms prefer surface contact with other protein atoms rather than with the solvent. This might correspond to the driving force for maximizing packing of the protein. The influence of the crystal packing, completeness of rotamer library and precise positioning of Cbeta atoms on the accuracy of side-chain prediction are examined. The Sccomp-S and Sccomp-I programs can be accessed through the Web (http://sgedg.weizmann.ac.il/sccomp.html) and are available for several platforms.

Algorithms↗

PubMedDate not supplied

ADME evaluation in drug discovery. 2. Prediction of partition coefficient by atom-additive approach based on atom-weighted solvent accessible surface areas.

A novel method for the calculations of 1-octanol/water partition coefficient (log P) of organic molecules has been presented here. The method, SLOGP v1.0, estimates the log P values by summing the contribution of atom-weighted solvent accessible surface areas (SASA) and correction factors. Altogether 100 atom/group types were used to classify atoms with different chemical environments, and two correlation factors were used to consider the intermolecular hydrophobic interactions and intramolecular hydrogen bonds. Coefficient values for 100 atom/group and two correction factors have been derived from a training set of 1850 compounds. The parametrization procedure for different kinds of atoms was performed as follows: first, the atoms in a molecule were defined to different atom/group types based on SMARTS language, and the correction factors were determined by substructure searching; then, SASA for each atom/group type was calculated and added; finally, multivariate linear regression analysis was applied to optimize the hydrophobic parameters for different atom/group types and correction factors in order to reproduce the experimental log P. The correlation based on the training set gives a model with the correlation coefficient (r) of 0.988, the standard deviation (SD) of 0.368 log units, and the absolute unsigned mean error of 0.261. Comparison of various procedures of log P calculations for the external test set of 138 organic compounds demonstrates that our method bears very good accuracy and is comparable or even better than the fragment-based approaches. Moreover, the atom-additive approach based on SASA was compared with the simple atom-additive approach based on the number of atoms. The calculated results show that the atom-additive approach based on SASA gives better predictions than the simple atom-additive one. Due to the connection between the molecular conformation and the molecular surface areas, the atom-additive model based on SASA may be a more universal model for log P estimation especially for large molecules.

Drug Design↗