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Results for “Solvent accessibility”

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PubMed1997

Computation of the solvent-accessible surface area of monomer nonionic contrast media. Consequences for used probe radius in the study of hydrophilic characteristics.

RATIONALE AND OBJECTIVES: The solvent-accessible surface areas of different monomer nonionic contrast media were calculated for different probe radii. By correlating these areas with an experimental (octanol/water partition coefficient) and a calculated parameter (COMB-C), implications for the radius of the probe volume are pointed out. METHODS: The solvent-accessible surface areas of seven monomer nonionic iodinated contrast media were calculated with GEPOL (a program able to calculate various molecular surfaces and volumes) for a wide range of probe radii of the solvent. These areas were correlated with the octanol/ water partition coefficient and COMB-C, a parameter describing the spatial distribution of the hydrophilic elements of a molecule. RESULTS: The correlation coefficients of the solvent-accessible surface areas (determined with the different probe radii) with the octanol/water partition coefficient and of the solvent-accessible surface areas (determined with the same probe radii) with COMB-C were good. This correlation was better for probe raddi of 3 A or more. CONCLUSIONS: COMB-C, a parameter designed earlier, correlated well with the hydrophilia of a monomer nonionic contrast molecule. It was shown that a probe radius of at least 3 A should be used when correlations with hydrophilic characteristics are studied, rather than a probe radius of 1.5 A, which is generally used in assessment of solubilities of molecules in biologic environment. Implications are discussed.

Computer Systems↗

PubMed1994

Conservation and prediction of solvent accessibility in protein families.

Currently, the prediction of three-dimensional (3D) protein structure from sequence alone is an exceedingly difficult task. As an intermediate step, a much simpler task has been pursued extensively: predicting 1D strings of secondary structure. Here, we present an analysis of another 1D projection from 3D structure: the relative solvent accessibility of each residue. We show that solvent accessibility is less conserved in 3D homologues than is secondary structure, and hence is predicted less accurately from automatic homology modeling; the correlation coefficient of relative solvent accessibility between 3D homologues is only 0.77, and the average accuracy of predictions based on sequence alignments is only 0.68. The latter number provides an effective upper limit on the accuracy of predicting accessibility from sequence when homology modeling is not possible. We introduce a neural network system that predicts relative solvent accessibility (projected onto ten discrete states) using evolutionary profiles of amino acid substitutions derived from multiple sequence alignments. Evaluated in a cross-validation test on 238 unique proteins, the correlation between predicted and observed relative accessibility is 0.54. Interpreted in terms of a three-state (buried, intermediate, exposed) description of relative accessibility, the fraction of correctly predicted residue states is about 58%. In absolute terms this accuracy appears poor, but given the relatively low conservation of accessibility in 3D families, the network system is not far from its likely optimal performance. The most reliably predicted fraction of the residues (50%) is predicted as accurately as by automatic homology modeling. Prediction is best for buried residues, e.g., 86% of the completely buried sites are correctly predicted as having 0% relative accessibility.

Biological Evolution↗

PubMed2002

Prediction of coordination number and relative solvent accessibility in proteins.

Knowing the coordination number and relative solvent accessibility of all the residues in a protein is crucial for deriving constraints useful in modeling protein folding and protein structure and in scoring remote homology searches. We develop ensembles of bidirectional recurrent neural network architectures to improve the state of the art in both contact and accessibility prediction, leveraging a large corpus of curated data together with evolutionary information. The ensembles are used to discriminate between two different states of residue contacts or relative solvent accessibility, higher or lower than a threshold determined by the average value of the residue distribution or the accessibility cutoff. For coordination numbers, the ensemble achieves performances ranging within 70.6-73.9% depending on the radius adopted to discriminate contacts (6A-12A). These performances represent gains of 16-20% over the baseline statistical predictor, always assigning an amino acid to the largest class, and are 4-7% better than any previous method. A combination of different radius predictors further improves performance. For accessibility thresholds in the relevant 15-30% range, the ensemble consistently achieves a performance above 77%, which is 10-16% above the baseline prediction and better than other existing predictors, by up to several percentage points. For both problems, we quantify the improvement due to evolutionary information in the form of PSI-BLAST-generated profiles over BLAST profiles. The prediction programs are implemented in the form of two web servers, CONpro and ACCpro, available at http://promoter.ics.uci.edu/BRNN-PRED/.

Amino Acids↗

PubMed2000

Solvent accessibility and purifying selection within proteins of Escherichia coli and Salmonella enterica.

The neutral theory of molecular evolution predicts that variation within species is inversely related to the strength of purifying selection, but the strength of purifying selection itself must be related to physical constraints imposed by protein folding and function. In this paper, we analyzed five enzymes for which polymorphic sequence variation within Escherichia coli and/or Salmonella enterica was available, along with a protein structure. Single and multivariate logistic regression models are presented that evaluate amino acid size, physicochemical properties, solvent accessibility, and secondary structure as predictors of polymorphism. A model that contains a positive coefficient of association between polymorphism and solvent accessibility and separate intercepts for each secondary-structure element is sufficient to explain the observed variation in polymorphism between sites. The model predicts an increase in the probability of amino acid polymorphism with increasing solvent accessibility for each protein regardless of physicochemical properties, secondary-structure element, or size of the amino acid. This result, when compared with the distribution of synonymous polymorphism, which shows no association with solvent accessibility, suggests a strong decrease in purifying selection with increasing solvent accessibility.

Aldose-Ketose Isomerases↗

PubMed1992

Residue solvent accessibilities in the unfolded polypeptide chain.

The difference of solvent accessibilities in the native and unfolded states of the protein is used as a measure of the hydrophobic contribution to the free energy of folding. We present a new approximation of amino acids solvent accessibilities in the unfolded state based on the 1-ns molecular dynamics simulation of Ala-X-Ala tripeptides at a temperature of 368 K. The standard accessibility values averaged from the molecular dynamics study are significantly lower from those previously obtained by considering only selected conformations of Ala-X-Ala tripeptides.

Amino Acid Sequence↗

PubMed2004

Allosteric changes in solvent accessibility observed in thrombin upon active site occupation.

The solvent accessibility of thrombin in its substrate-free and substrate-bound forms has been compared by amide hydrogen/deuterium (H/(2)H) exchange. The optimized inhibitor peptide dPhe-Pro-Arg chloromethyl ketone (PPACK) was used to simulate the substrate-bound form of thrombin. These studies were motivated by the lack of observed changes in the active site of thrombin in the crystal structure of the thrombin-thrombomodulin complex. This result appeared to contradict amide exchange studies on the thrombin-thrombomodulin complex that suggested subtle changes occur in the active site loops upon thrombomodulin binding. Our results show that two active site loops, residues 214-222 and residues 126-132, undergo decreases in solvent accessibility due to steric contacts with PPACK substrate. However, we also observe two regions outside the active site undergoing solvent protection upon substrate binding. The first region corresponds to anion binding exosite 1, and the second is a beta-strand-containing loop which runs through the core of the molecule and contains Trp141 which makes critical contacts with anion binding exosite 1. These results indicate two pathways of allosteric change that connect the active site to the distal anion binding exosite 1.

Allosteric Regulation↗

PubMed1987

Unfolding pathway of myoglobin: effect of denaturants on solvent accessibility to tyrosyl residues detected by second-derivative spectroscopy.

The effects of denaturants on the solvent accessibility to tyrosyl residues of apomyoglobin have been examined by means of second-derivative spectroscopy in the near-ultraviolet. Three apomyoglobins, i.e., sperm whale, horse, and tuna, were selected because of the different distribution of tyrosyl residues in their primary structure. The results are consistent with the occurrence of two independent consecutive events in the guanidine-induced denaturation pattern of apomyoglobin. The first event, which is responsible for the lack of the ability to bind the heme, has been proved to involve conformational changes in both the domains, i.e., segments 1-79 and 80-153, identified in the myoglobin molecule. However, the conformational changes are not of the same type. In fact, the solvent accessibility to tyrosine HC2 is increased probably because of a partial unfolding of the 80-153 domain. Conversely, the solvent accessibility to tyrosine B2 is decreased, thus indicating that a refolding occurs in some region of the N-terminal moiety (1-79 domain) of the molecule.

Animals↗

PubMed1985

Solvent accessibility to flavin in oxynitrilase.

Oxynitrilase containing 2-thioFAD [C(2) = S] in place of FAD exhibits catalytic activity similar to that of native enzyme. Reaction of methyl methanethiolsulfonate with 2-thioFAD bound to oxynitrilase results in the formation of the corresponding flavin disulfide [C(2)-SSCH3]. Normal flavin [C(2) = O] is formed by reacting 2-thioFAD oxynitrilase with m-chloroperoxybenzoate or H2O2. Both reactions proceed via a spectrally detectable flavin 2-S-oxide intermediate [C(2) = S+-O-], but sizable amounts of this intermediate accumulate only in the m-chloroperoxybenzoate reaction (about 40%). While similar reactions have been reported with free 2-thioflavin, kinetic and other data indicate that the oxynitrilase reactions occur with intact enzyme. This shows that the 2-position of the pyrimidine ring in the bound coenzyme is accessible to solvent. The data are consistent with previous studies on the reaction of peroxides with oxynitrilase-bound 5-deazaFAD which show that the pyrimidine ring is accessible at position 4. Analogous studies indicate that the pyrimidine ring is buried in the case of flavin bound to lactate oxidase, since the data indicate that both positions 2 and 4 are inaccessible to solvent.

Aldehyde-Lyases↗

PubMed2000

Predicting residue solvent accessibility from protein sequence by considering the sequence environment.

The solvent accessibility of each residue is predicted on the basis of the protein sequence. A set of 338 monomeric, non-homologous and high-resolution protein crystal structures is used as a learning set and a jackknife procedure is applied to each entry. The prediction is based on the comparison of the observed and the average values of the solvent-accessible area. It appears that the prediction accuracy is significantly improved by considering the residue types preceding and/or following the residue whose accessibility must be predicted. In contrast, the separate treatment of different secondary structural types does not improve the quality of the prediction. It is furthermore shown that the residue accessibility is much better predicted in small than in larger proteins. Such a discrepancy must be carefully considered in any algorithm for predicting residue accessibility.

Amino Acid Sequence↗

PubMed2001

Solvent accessibility of the thrombin-thrombomodulin interface.

The kinetics of solvent accessibility at the protein-protein interface between thrombin and a fragment of thrombomodulin, TMEGF45, have been monitored by amide hydrogen/deuterium (H/2H) exchange detected by MALDI-TOF mass spectrometry. The interaction is rapid and reversible, requiring development of theory and experimental methods to distinguish H/2H exchange due to solvent accessibility at the interface from H/2H exchange due to complex dissociation. Association and dissociation rate constants were measured by surface plasmon resonance and amide H/2H exchange rates were measured at different pH values and concentrations of TMEGF45. When essentially 100% of the thrombin was bound to TMEGF45, two segments of thrombin became completely solvent-inaccessible, as evidenced by the pH insensitivity of the amide H/2H exchange rates. These segments form part of anion-binding exosite I and contain the residues for which alanine substitution abolishes TM binding. Several other regions of thrombin showed slowing of amide exchange upon TMEGF45 binding, but the exchange remained pH-dependent, suggesting that these regions of thrombin were rendered only partially solvent-inaccessible by TMEGF45 binding. These partially inaccessible regions of thrombin form both surface and buried contacts into the active site of thrombin and contain residues implicated in allosteric changes in thrombin upon TM binding.

Allosteric Site↗

PubMed2005

Linear regression models for solvent accessibility prediction in proteins.

The relative solvent accessibility (RSA) of an amino acid residue in a protein structure is a real number that represents the solvent exposed surface area of this residue in relative terms. The problem of predicting the RSA from the primary amino acid sequence can therefore be cast as a regression problem. Nevertheless, RSA prediction has so far typically been cast as a classification problem. Consequently, various machine learning techniques have been used within the classification framework to predict whether a given amino acid exceeds some (arbitrary) RSA threshold and would thus be predicted to be "exposed," as opposed to "buried." We have recently developed novel methods for RSA prediction using nonlinear regression techniques which provide accurate estimates of the real-valued RSA and outperform classification-based approaches with respect to commonly used two-class projections. However, while their performance seems to provide a significant improvement over previously published approaches, these Neural Network (NN) based methods are computationally expensive to train and involve several thousand parameters. In this work, we develop alternative regression models for RSA prediction which are computationally much less expensive, involve orders-of-magnitude fewer parameters, and are still competitive in terms of prediction quality. In particular, we investigate several regression models for RSA prediction using linear L1-support vector regression (SVR) approaches as well as standard linear least squares (LS) regression. Using rigorously derived validation sets of protein structures and extensive cross-validation analysis, we compare the performance of the SVR with that of LS regression and NN-based methods. In particular, we show that the flexibility of the SVR (as encoded by metaparameters such as the error insensitivity and the error penalization terms) can be very beneficial to optimize the prediction accuracy for buried residues. We conclude that the simple and computationally much more efficient linear SVR performs comparably to nonlinear models and thus can be used in order to facilitate further attempts to design more accurate RSA prediction methods, with applications to fold recognition and de novo protein structure prediction methods.

Amino Acids↗

PubMed2006

Atom-wise statistics and prediction of solvent accessibility in proteins.

In this work, we explore a novel method to broaden the scope of sequence-based predictions of solvent accessibility or accessible surface area (ASA) to the atomic level. All 167 heavy atoms from the 20 types of amino acid residues in proteins have been studied. An analysis of ASA distribution of these atomic groups in different proteins has been performed and rotamer-style libraries have been developed. We observe that the ASA of some atomic groups (e.g., backbone C and N atoms) can be estimated from the sequence environment within a mean absolute error of 2-3 angstroms(2). However, some side chain atoms such as CG in Pro, NH1 in Arg and NE2 in Gln show a strong variability making it more difficult to estimate their ASA from sequence environment. In general, the prediction of ASA becomes more difficult for atomic positions at the side chain extremities of long amino acid residues (aromatic side chain terminals being the exception). Several atomic groups are frequently exposed to solvent. Some of them have a bimodal distribution, suggesting two stable conformations in terms of their solvent exposure. More detailed understanding and prediction of solvent accessibility, i.e., at an atomic level is expected to help in bioinformatics approaches to structure prediction, functional relevance of atomic solvent accessibilities and other interaction analyses.

Amino Acids↗

PubMed1983

Solvent-accessible surfaces of proteins and nucleic acids.

A method is presented for analytically calculating a smooth, three-dimensional contour about a molecule. The molecular surface envelope may be drawn on either color raster computer displays or real-time vector computer graphics systems. Molecular areas and volumes may be computed analytically from this surface representation. Unlike most previous computer graphics representations of molecules, which imitate wire models or space-filling plastic spheres, this surface shows only the atoms that are accessible to solvent. This analytical method extends the earlier dot surface numerical algorithm, which has been applied in enzymology, rational drug design, immunology, and understanding DNA base sequence recognition.

Aspartate Carbamoyltransferase↗

PubMed2005

Prediction of protein relative solvent accessibility with a two-stage SVM approach.

Information on relative solvent accessibility (RSA) of amino acid residues in proteins provides valuable clues to the prediction of protein structure and function. A two-stage approach with support vector machines (SVMs) is proposed, where an SVM predictor is introduced to the output of the single-stage SVM approach to take into account the contextual relationships among solvent accessibilities for the prediction. By using the position-specific scoring matrices (PSSMs) generated by PSI-BLAST, the two-stage SVM approach achieves accuracies up to 90.4% and 90.2% on the Manesh data set of 215 protein structures and the RS126 data set of 126 nonhomologous globular proteins, respectively, which are better than the highest published scores on both data sets to date. A Web server for protein RSA prediction using a two-stage SVM method has been developed and is available (http://birc.ntu.edu.sg/~pas0186457/rsa.html).

Amino Acids↗

PubMed1998

Predictions of secondary structure and solvent accessibility of the light chain of the clostridial neurotoxins.

Predictions were made of the secondary, two-dimensional (2-D) structures and side-chain solvent accessibilities of the light (L) chains of the clostridial neurotoxins (botulinum neurotoxin serotypes A-G and tetanus neurotoxin). An artificial neural network was used to make these predictions from a multiple alignment of their primary structures and was the approach used in making successful predictions for the C-fragments of these neurotoxins (Lebeda et al., J. Prot. Chem., 17:311, 1998). We also exploited the fact that the L-chains are Zn-dependent proteases. Although no other metalloproteases were found to be sequentially homologous to these neurotoxin L-chains, a sequence clustering algorithm showed that several bacterially derived Zn-dependent proteases, including thermolysin, were the most similar. A 2-D structure topology map for the type A L-chain was constructed by using thermolysin as a design template. As in thermolysin, the region containing the Zn-binding sequence motif, which is part of the active site in these neurotoxins, was predicted to be minimally solvent accessible. On the other hand, the locations of residues with highly exposed side chains were predicted to occur in non-periodic structure elements. Together, these 2-D structure and solvent accessibility predictions can be used to identify important solvent-exposed regions of the L-chain. These regions may include sites that interact with residues of the neurotoxin heavy chain, sites that bind to vesicle-docking substrates or sites that form antibody epitopes.

Algorithms↗

PubMed2003

Real value prediction of solvent accessibility from amino acid sequence.

The solvent accessibility of amino acid residues has been predicted in the past by classifying them into exposure states with varying thresholds. This classification provides a wide range of values for the accessible surface area (ASA) within which a residue may fall. Thus far, no attempt has been made to predict real values of ASA from the sequence information without a priori classification into exposure states. Here, we present a new method with which to predict real value ASAs for residues, based on neighborhood information. Our real value prediction neural network could estimate the ASA for four different nonhomologous, nonredundant data sets of varying size, with 18.0-19.5% mean absolute error, defined as per residue absolute difference between the predicted and experimental values of relative ASA. Correlation between the predicted and experimental values ranged from 0.47 to 0.50. It was observed that the ASA of a residue could be predicted within a 23.7% mean absolute error, even when no information about its neighbors is included. Prediction of real values answers the issue of arbitrary choice of ASA state thresholds, and carries more information than category prediction. Prediction error for each residue type strongly correlates with the variability in its experimental ASA values.

Amino Acid Sequence↗

PubMed1996

Evaluation of Solvent Accessibility to the [Fe(4)S(4)] Binding Pocket in Native and Tyr19 Mutant High Potential Iron Proteins by (1)H-(15)N HMQC and (19)F NMR Experiments.

The solvent accessibility of Chromatium vinosumhigh potential iron protein (HiPIP) has been investigated by use of (1)H-(15)N HMQC, and (19)F NMR spectroscopy. These NMR experiments indicate that solvent accessibility to the cluster core is similar, and minimal, for the reduced and oxidized states of native HiPIP, but increases significantly for mutant proteins (Tyr19Leu and Tyr19His). These results support a proposed role [Agarwal, A.; Li, D.; Cowan, J. A. Proc. Natl. Acad. Sci. U.S.A. 1995, 92, 9440-9444] for Tyr19 in maintaining hydrolytic stability of the [Fe(4)S(4)] cluster, and demonstrate a general strategy for mapping out the solvent accessibility of protein-bound metalloredox prosthetic centers.

Journal Article↗

PubMed1998

Identification of protein-protein interfaces by decreased amide proton solvent accessibility.

Matrix-assisted laser desorption ionization-time-of-flight mass spectrometry was used to identify peptic fragments from protein complexes that retained deuterium under hydrogen exchange conditions due to decreased solvent accessibility at the interface of the complex. Short deuteration times allowed preferential labeling of rapidly exchanging surface amides so that primarily solvent accessibility changes and not conformational changes were detected. A single mass spectrum of the peptic digest mixture was analyzed to determine the deuterium content of all proteolytic fragments of the protein. The protein-protein interface was reliably indicated by those peptides that retained more deuterons in the complex compared with control experiments in which only one protein was present. The method was used to identify the kinase inhibitor [PKI(5-24)] and ATP-binding sites in the cyclic-AMP-dependent protein kinase. Three overlapping peptides identified the ATP-binding site, three overlapping peptides identified the glycine-rich loop, and two peptides identified the PKI(5-24)-binding site. A complex of unknown structure also was analyzed, human alpha-thrombin bound to an 83-aa fragment of human thrombomodulin [TMEGF(4-5)]. Five peptides from thrombin showed significantly decreased solvent accessibility in the complex. Three peptides identified the anion-binding exosite I, confirming ligand competition experiments. Two peptides identified a new region of thrombin near the active site providing a potential mechanism of how thrombomodulin alters thrombin substrate specificity.

Amino Acid Sequence↗