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Results for “Solvent accessibility”

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PubMed2000

Leap-dynamics: efficient sampling of conformational space of proteins and peptides in solution.

A molecular simulation scheme, called Leap-dynamics, that provides efficient sampling of protein conformational space in solution is presented. The scheme is a combined approach using a fast sampling method, imposing conformational 'leaps' to force the system over energy barriers, and molecular dynamics (MD) for refinement. The presence of solvent is approximated by a potential of mean force depending on the solvent accessible surface area. The method has been successfully applied to N-acetyl-L-alanine-N-methylamide (alanine dipeptide), sampling experimentally observed conformations inaccessible to MD alone under the chosen conditions. The method predicts correctly the increased partial flexibility of the mutant Y35G compared to native bovine pancreatic trypsin inhibitor. In particular, the improvement over MD consists of the detection of conformational flexibility that corresponds closely to slow motions identified by nuclear magnetic resonance techniques.

Alanine↗

PubMed1992

Heat capacity changes and hydrophobic interactions in the binding of FK506 and rapamycin to the FK506 binding protein.

Differential interactions among nonpolar moieties at protein/ligand interfaces, and of these nonpolar groups with water, collectively termed hydrophobic interactions, are widely believed to make important energetic contributions to the stability of protein/ligand complexes. Quantitative estimates of hydrophobic interactions, and an evaluation of their structural basis, are essential for obtaining structure-based predictions of the free energies of binding for the purpose of drug design. Two largely nonpolar, immunosuppressive agents, FK506 and rapamycin, each bind with high affinity to a common hydrophobic pocket on a small peptidylproline cis-trans isomerase known as FK506 binding protein (FKBP-12) and inhibit its activity. In an effort to elucidate the structural features of these ligands responsible for the observed energetics, we have undertaken an investigation of the thermodynamics of binding of FK506 and rapamycin to FKBP-12. Enthalpies of binding have been determined by high-precision titration calorimetry over a range of temperature, allowing estimates of heat capacity changes. By analyzing the distribution of changes in solvent-accessible surface area upon binding of FK506 to FKBP-12 from crystallographic data, it is found that 99% of the net surface buried upon binding involves nonpolar groups. This leads to a heat capacity change of FK506 binding, normalized to the amount of nonpolar surface, of -0.40 +/- 0.02 cal.K-1.mol-1.A-2 (1 cal = 4.18 J), a value similar to that obtained for the aqueous dissolution of hydrophobic substances. Our observations are discussed in view of the general nature of hydrophobic interaction processes.

Calorimetry↗

PubMed2001

Visualizing the solvent-inaccessible core of a group II intron ribozyme.

Group II introns are well recognized for their remarkable catalytic capabilities, but little is known about their three-dimensional structures. In order to obtain a global view of an active enzyme, hydroxyl radical cleavage was used to define the solvent accessibility along the backbone of a ribozyme derived from group II intron ai5gamma. These studies show that a highly homogeneous ribozyme population folds into a catalytically compact structure with an extensively internalized catalytic core. In parallel, a model of the intron core was built based on known tertiary contacts. Although constructed independently of the footprinting data, the model implicates the same elements for involvement in the catalytic core of the intron.

Base Sequence↗

PubMed1998

Prediction of binding affinities for TIBO inhibitors of HIV-1 reverse transcriptase using Monte Carlo simulations in a linear response method.

Monte Carlo (MC) simulations in combination with a linear response approach were used to estimate the free energies of binding for a series of 12 TIBO nonnucleoside inhibitors of HIV-1 reverse transcriptase. Separate correlations were made for the R6 and S6 absolute conformations of the inhibitors, as well as for the analogous N6-monoprotonated species. Models based upon the neutral unbound inhibitors produced overall better fits to experimental values than did those using the protonated unbound inhibitors, with only slight differences between the neutral R6 and S6 cases. The best results were obtained with a three-parameter linear response equation containing van der Waals (alpha), electrostatic (beta), and solvent accessible surface area (SASA, gamma) terms. The averaged (R6 and S6) rms error was approximately 0.88 kcal/mol for the observed range of 4.06 kcal/mol in inhibitor activities. The averaged values of alpha, beta, and gamma were -0.150, 0.114, and 0. 0286, respectively. Omission of the alpha term gave beta 0.152 and gamma 0.022 with a rms of 0.92. The unweighted van der Waals components were found to be highly attractive but failed to correlate well across the series of inhibitors. Contrastingly, while the electrostatic components are all repulsive, they show a direct correlation with inhibitor activity as measured by DeltaGbinding. The role of gamma is primarily to produce an overall negative binding energy, and it can effectively be replaced with a negative constant. During the MC simulations of the unbound solvated inhibitors, the R6 and S6 absolute conformations do not interconvert due to the formation of a favorable hydrogen bond to solvent. In the complex, however, interconversion of these conformations of the inhibitor is observed during the course of the simulations, a phenomenon which is apparently not observed in the crystalline state of the complex. Hydrogen bonding of the inhibitor to the backbone NH of K101 and the lack of such an interaction with the C=O of K101 or with solvent correlate with enhanced activity, as does the ability to assume a number of different orientations of the inhibitor dimethylallyl moiety with respect to residues Y181 and Y188 while retaining contact with W229. Overall, the use of a combination of MC simulation with a linear response method shows promise as a relatively rapid means of estimating inhibitor activities. This approach should be useful in the preliminary evaluation of potential modifications to known inhibitors to enhance activity.

Anti-HIV Agents↗

PubMed1989

Absence of large-scale conformational change upon limited proteolysis of ovalbumin, the prototypic serpin.

1H and 31P NMR spectroscopies have been used to examine the effects of limited proteolysis with subtilisin Carlsberg on the global conformation of ovalbumin and on the local environment of phosphoserine 344, a residue two positions removed from the site of proteolysis. Such limited proteolysis has been shown to result in excision of a hexapeptide from the region of the protein that, in other serine protease inhibitors (serpins), contains the reactive center. Based on the structure of the related serpin alpha 1-antitrypsin, it has been predicted that phosphoserine 344 should undergo a large change in environment upon proteolysis of ovalbumin (Löbermann, H., Tokuoka, R., Deisenhofer, J., and Huber, R. (1984) J. Mol. Biol. 177, 531-550). Proteolysis of ovalbumin produces a small upfield shift (0.15 ppm) of the 31P resonance of phosphoserine 344. In addition, the pKa of phosphoserine 344 is raised by 0.1 pH unit. At pH 8.5, phosphoserine 344 in cleaved ovalbumin (plakalbumin) is as accessible to hydrolysis by Escherichia coli alkaline phosphatase as it is in native ovalbumin. 1H NMR shows that dephosphorylation of serine 344 has an imperceptible effect on the protein's conformation. Similarly, little effect on conformation is seen by 1H NMR upon proteolysis of ovalbumin. These findings suggest that ovalbumin does not undergo a marked conformational change analogous to that inferred for the related members of the serpin superfamily, alpha 1-antitrypsin and antithrombin III, nor do the residues close to the site of proteolysis appear to change environment from that of an exposed loop to a buried strand of beta-sheet. These findings are not consistent with the hypothesis of Carrell and Owen ((1985) Nature 317, 730-732) for the role of the exposed loop in serpins of directly facilitating conformational change upon cleavage of the loop. Instead, it is proposed that cleavage of the exposed loop alters the solvent accessibility of residues formerly covered by the loop and that this provides the thermodynamic impetus for conformational change, perhaps by disruption of a salt bridge crucial to the integrity of the native structure.

Animals↗

PubMed2003

Analysis of the effect of electrostatic energy truncation in molecular dynamics simulations of immunoglobulin G light chain dimer.

Molecular dynamics (MD) simulations of immunoglobulin G (IgG) light chain dimer using particle mesh Ewald (PME) and cutoff methods of treating electrostatic interactions were performed. The results indicate that structural parameters (RMSD, radius of gyration, solvent accessible surface) are very similar for both schemes; however, PME simulation shows increased mobility of side chains. This leads to larger fluctuations in the distance between the monomers in the dimer molecule, and, as a consequence, results in decreased number of interactions across the dimer interface. The wall clock time of the simulations was also compared. It was shown that the PME method is approximately 30% faster than the cutoff method for the system studied on a single processor.

Computer Simulation↗

PubMed1996

The application of different solvation and electrostatic models in molecular dynamics simulations of ubiquitin: how well is the X-ray structure "maintained"?

We present molecular dynamics simulations on ubiquitin with explicit solvent molecules and investigate the influence of different force fields [Weiner et al. (J. Am. Chem. Soc. 106:765-784, 1984; J. Comput. Chem. 7:230-252, 1986) vs. Cornell et al. (J. Am. Chem. Soc. 117:5179-5197, 1995)], different treatments of the long-range electrostatic interaction (8 A cutoff vs. particle mesh Ewald), and different solvation models (periodic box vs. small shell of water molecules) on the structure and the dynamics of the protein. Structural data are monitored by atomic root mean square deviations (RMSDs) from the crystal structure, the radius of gyration, the solvent-accessible surface area, and the pattern of the backbone hydrogen bonds. The dynamic behavior is assessed by the atomic fluctuations and the order parameters of the N-H backbone vectors. With the Cornell et al. force field and a periodic box model, the simulated structures stay much closer to the experimental X-ray structure than with the older Weiner et al. force field. A further improvement of the simulation is found when the electrostatic interaction is evaluated with the particle mesh Ewald method; after 1.2 ns of simulation the backbone RMSD amounts to only 1.13 A. The analysis of the dynamic parameters shows that this good structural agreement is not due to a damping of internal motion in the protein. For a given length of simulation time, the shell models achieve an agreement between simulated and experimental structures that is comparable to the best models that employ a periodic box of solvent models. However, compared with the box models, the fluctuations of the protein atoms in the shell models are smaller, and only with simulation times as long as 2 ns do they become of comparable size to the experimental ones.

Computer Simulation↗

PubMed2006

What role do surfaces play in GB models? A new-generation of surface-generalized born model based on a novel gaussian surface for biomolecules.

We have developed a version of our surface generalized Born (SGB) model that employs a Gaussian surface, as opposed to the van der Waals surface used previously. The Gaussian surface is smooth and its properties are analytically differentiable with respect to the positions of atoms. A significant advantage of a solvent model based on this analytically differentiable surface is the availability of analytical gradients of the surface and solvation forces. An efficient and robust algorithm is designed to construct and triangulate the Gaussian surface for large biomolecules with arbitrary shapes, and to compute the various terms required for energy gradients. The Gaussian surface is shown to better mimic the boundary between the solute and solvent by properly addressing solvent accessibility, as is demonstrated by comparisons with standard Poisson-Boltzmann calculations for proteins of different sizes. These results also demonstrate that surface definition is a dominant contribution to differences between GB and PB calculations, especially if the system is large. Application of the new surface to prediction of long loop regions is presented, and significant improvement in the energetics is seen compared with results obtained using the van der Waals surface, even in the absence of optimized empirical correction terms that were used in the latter calculations.

Algorithms↗

PubMed1990

Solvation effects on the sequence variability of DNA double helical conformations.

The role of solvation on the sequence dependent conformational variabilities in DNA has been studied by calculating hydration free energies from solvent accessible surface areas for several base steps, as a function of various helical parameters, roll, twist and propeller twist. The results of roll calculations suggest opposite trends for AA and GG steps, with the former tending to have a compressed minor groove and the latter a compressed major groove. These trends are consistent with the experimental findings on sequence preferences and the nature of anisotropic bending of DNA observed in nucleosomes (Drew, H.R. and Travers, A.A., J. Mol. Biol. 186, 773-790 (1985); Satchwell, S.C., Drew, H.R. and Travers, A.A., J. Mol. Biol. 191, 659-675 (1986)) and CAP-DNA interactions (Gartenberg, M.R. and Crothers, D.M., Nature 333, 824-829, (1988)). Solvation energy profiles also indicate preferences for the base pairs in GG and AA steps to adopt low and high propeller twists, respectively. Such agreements may either reflect a coincidence of solvation effects with other energy terms or a dominance of solvent effects. The results are discussed in the context of the crystallographic observations of structural tendencies.

DNA, Superhelical↗

PubMed2001

Multiple functions for the C terminus of the PsaD subunit in the cyanobacterial photosystem I complex.

PsaD subunit of Synechocystis sp PCC 6803 photosystem I (PSI) plays a critical role in the stability of the complex and is part of the docking site for ferredoxin (Fd). In the present study we describe major physiological and biochemical effects resulting from mutations in the accessible C-terminal end of the protein. Four basic residues were mutated: R111, K117, K131, and K135, and a large 36-amino acid deletion was generated at the C terminus. PSI from R111C mutant has a 5-fold decreased affinity for Fd, comparable with the effect of the C terminus deletion, and NADP+ is photoreduced with a 2-fold decreased rate, without consequence on cell growth. The K117A mutation has no effect on the affinity for Fd, but decreases the stability of PsaE subunit, a loss of stability also observed in R111C and the deletion mutants. The double mutation K131A/K135A does not change Fd binding and reduction, but decreases the overall stability of PSI and impairs the cell growth at temperatures above 30 degrees C. Three mutants, R111C, K117A, and the C-terminal deleted exhibit a higher content of the trimeric form of PSI, in apparent relation to the removal of solvent accessible positive charges. Various regions in the C terminus of cyanobacterial PsaD thus are involved in Fd strong binding, PSI stability, and accumulation of trimeric PSI.

Cyanobacteria↗

PubMed2003

An improved protein decoy set for testing energy functions for protein structure prediction.

We have improved the original Rosetta centroid/backbone decoy set by increasing the number of proteins and frequency of near native models and by building on sidechains and minimizing clashes. The new set consists of 1,400 model structures for 78 different and diverse protein targets and provides a challenging set for the testing and evaluation of scoring functions. We evaluated the extent to which a variety of all-atom energy functions could identify the native and close-to-native structures in the new decoy sets. Of various implicit solvent models, we found that a solvent-accessible surface area-based solvation provided the best enrichment and discrimination of close-to-native decoys. The combination of this solvation treatment with Lennard Jones terms and the original Rosetta energy provided better enrichment and discrimination than any of the individual terms. The results also highlight the differences in accuracy of NMR and X-ray crystal structures: a large energy gap was observed between native and non-native conformations for X-ray structures but not for NMR structures.

Algorithms↗

PubMedDate not supplied

Importance of native-state topology for determining the folding rate of two-state proteins.

Understanding the relationship between amino acid sequences and folding rate of proteins is a challenging task similar to protein folding problem. In this work, we have analyzed the relative importance of protein sequence and structure for predicting the protein folding rates in terms of amino acid properties and contact distances, respectively. We found that the parameters derived with protein sequence (physical-chemical, energetic, and conformational properties of amino acid residues) show very weak correlation (|r| < 0.39) with folding rates of 28 two-state proteins, indicating that the sequence information alone is not sufficient to understand the folding rates of two-state proteins. However, the maximum positive correlation obtained for the properties, number of medium-range contacts, and alpha-helical tendency reveals the importance of local interactions to initiate protein folding. On the other hand, a remarkable correlation (r varies from -0.74 to -0.88) has been obtained between structural parameters (contact order, long-range order, and total contact distance) and protein folding rates. Further, we found that the secondary structure content and solvent accessibility play a marginal role in determining the folding rates of two-state proteins. Multiple regression analysis carried out with the combination of three properties, beta-strand tendency, enthalpy change, and total contact distance improved the correlation to 0.92 with protein folding rates. The relative importance of existing methods along with multiple-regression model proposed in this work will be discussed. Our results demonstrate that the native-state topology is the major determinant for the folding rates of two-state proteins.

Amino Acids↗

PubMed2002

A reactivity pattern for discrimination of ER agonism and antagonism based on 3-D molecular attributes.

Various models have been developed to predict the relative binding affinity (RBA) of chemicals to estrogen receptors (ER). These models can be used to prioritize chemicals for further tiered biological testing to assess the potential for endocrine disruption. One shortcoming of models predicting RBA has been the inability to distinguish potential receptor antagonism from agonism, and hence in vivo response. It has been suggested that steroid receptor antagonists are less compact than agonists; thus, ER binding of antagonists may prohibit proper alignment of receptor protein helices preventing subsequent transactivation. The current study tests the theory of chemical bulk as a defining parameter of antagonism by employing a 3-D structural approach for development of reactivity patterns for ER antagonists and agonists. Using a dataset of 23 potent ER ligands (16 agonists, 7 antagonists), molecular parameters previously found to be associated with ER binding affinity, namely global (E(HOMO)) and local (donor delocalizabilities and charges) electron donating ability of electronegative sites and steric distances between those sites, were found insufficient to discriminate ER antagonists from agonists. However, parameters related to molecular bulk, including solvent accessible surface and negatively charged Van der Waal's surface, provided reactivity patterns that were 100% successful in discriminating antagonists from agonists in the limited data set tested. The model also shows potential to discriminate pure antagonists from partial agonist/antagonist structures. Using this exploratory model it is possible to predict additional chemicals for their ability to bind but inactivate the ER, providing a further tool for hypothesis testing to elucidate chemical structural characteristics associated with estrogenicity and anti-estrogenicity.

Animals↗

PubMed2006

Energetic basis of molecular recognition in a DNA aptamer.

The thermal stability and ligand binding properties of the L-argininamide-binding DNA aptamer (5'-GATCGAAACGTAGCGCCTTCGATC-3') were studied by spectroscopic and calorimetric methods. Differential calorimetric studies showed that the uncomplexed aptamer melted in a two-state reaction with a melting temperature T(m)=50.2+/-0.2 degrees C and a folding enthalpy DeltaH(0)(fold)=-49.0+/-2.1 kcal mol(-1). These values agree with values of T(m)=49.6 degrees C and DeltaH(0)(fold)=-51.2 kcal mol(-1) predicted for a simple hairpin structure. Melting of the uncomplexed aptamer was dependent upon salt concentration, but independent of strand concentration. The T(m) of aptamer melting was found to increase as L-argininamide concentrations increased. Analysis of circular dichroism titration data using a single-site binding model resulted in the determination of a binding free energy DeltaG(0)(bind)=-5.1 kcal mol(-1). Isothermal titration calorimetry studies revealed an exothermic binding reaction with DeltaH(0)(bind)=-8.7 kcal mol(-1). Combination of enthalpy and free energy produce an unfavorable entropy of -TDeltaS(0)=+3.6 kcal mol(-1). A molar heat capacity change of -116 cal mol(-1) K(-1) was determined from calorimetric measurements at four temperatures over the range of 15-40 degrees C. Molecular dynamics simulations were used to explore the structures of the unligated and ligated aptamer structures. From the calculated changes in solvent accessible surface areas of these structures a molar heat capacity change of -125 cal mol(-1) K(-1) was calculated, a value in excellent agreement with the experimental value. The thermodynamic signature, along with the coupled CD spectral changes, suggest that the binding of L-argininamide to its DNA aptamer is an induced-fit process in which the binding of the ligand is thermodynamically coupled to a conformational ordering of the nucleic acid.

Aptamers, Nucleotide↗

PubMed2006

Homology modeling of tubulin: influence predictions for microtubule's biophysical properties.

Using comparative modeling, we have generated structural models of 475 alpha and beta tubulins. Using these models, we observed a global, structural similarity between the tubulin isotypes. However, a number of subtle differences in the isotypes physical properties, including net electric charges, solvent accessible surface areas, and electric dipole moments were also apparent. In order to examine the roles that these properties may play in microtubule (MT) assembly and stability, we have created a model to evaluate the dipole-dipole interaction energies of varying MT lattice conformations, using human tubulin isotypes as particularly important examples. We conclude that the dipole moments of each tubulin isotype may influence their functional characteristics within the cell, resulting in differences for MT assembly kinetics and stability.

Biophysics↗

PubMed2001

Prediction of blood-brain partitioning using Monte Carlo simulations of molecules in water.

The brain-blood partition coefficient (log BB) is a determining factor for the efficacy of central nervous system acting drugs. Since large-scale experimental determination of log BB is unfeasible, alternative evaluation methods based on theoretical models are desirable. Toward this direction, we propose a model that correlates log BB with physically significant descriptors for 76 structurally diverse molecules. We employ Monte Carlo simulations of the compounds in water to calculate such properties as the solvent-accessible surface area (SASA), the number of hydrogen bond donors and acceptors, the solute dipole, and the hydrophilic, hydrophobic and amphiphilic components of SASA. The physically significant descriptors are identified and a quantitative structure-prediction relationship is constructed that predicts log BB. This work demonstrates that computer simulations can be employed in a semi-empirical framework to build predictive QSPRs that shed light on the physical mechanism of biomolecular phenomena.

Animals↗

PubMed1996

Watching proteins move using site-directed spin labeling.

Site-directed spin labeling of proteins has proven to be a practical means for determining secondary structure and its orientation; surfaces of tertiary interactions; inter-residue distances; chain topology and depth of a given side chain from the membrane/aqueous surface in membrane proteins; and local electrostatic potentials at solvent-exposed sites. Moreover, the mobility of a side chain together with its solvent-accessibility may serve to uniquely identify the topographical location of specific residues in the protein fold. Future spectral analysis should permit a quantitative estimation of the contribution of backbone flexibility to the overall side-chain dynamics. The ability to time-resolve the structural features mentioned above makes SDSL a powerful approach for exploring the evolution of structure on the millisecond time scale. We anticipate future applications to the study of protein folding both in solution and in chaperone-mediated systems.

Electron Spin Resonance Spectroscopy↗

PubMed2004

The mechanism of target base attack in DNA cytosine carbon 5 methylation.

We measured the tritium exchange reaction on cytosine C(5) in the presence of AdoMet analogues to investigate the catalytic mechanism of the bacterial DNA cytosine methyltransferase M.HhaI. Poly(dG-dC) and poly(dI-dC) substrates were used to investigate the function of the active site loop (residues 80-99), stability of the extrahelical base, base flipping mechanism, and processivity on DNA substrates. On the basis of several experimental approaches, we show that methyl transfer is the rate-limiting pre-steady-state step. Further, we show that the active site loop opening contributes to the rate-limiting step during multiple cycles of catalysis. Target base activation and nucleophilic attack by cysteine 81 are fast and readily reversible. Thus, the reaction intermediates involving the activated target base and the extrahelical base are in equilibrium and accumulate prior to the slow methyl transfer step. The stability of the activated target base depends on the active site loop closure, which is dependent on the hydrogen bond between isoleucine 86 and the guanine 5' to the target cytosine. These interactions prevent the premature release of the extrahelical base and uncontrolled solvent access; the latter modulates the exchange reaction and, by implication, the mutagenic deamination reaction. The processive catalysis by M.HhaI is also regulated by the interaction between isoleucine 86 and the DNA substrate. Nucleophilic attack by cysteine 81 is partially rate limiting when the target base is not fully stabilized in the extrahelical position, as observed during the reaction with the Gln(237)Trp mutant or in the cytosine C(5) exchange reaction in the absence of the cofactor.

Carbon↗