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18 recordsLinked to original sources
PubMed1978

Hydrogen exchange kinetics of human hemoglobins. The pH dependence of solvent accessibility in cyanomet-, oxy-, and deoxyhemoglobin.

The hydrogen exchange kinetics of human oxy-, deoxy-, and cyanomethemoglobin have been measured as a function of pH by the tritium tracer method. At 5 degrees C and in phosphate buffer both liganded and unliganded forms of ferrohemoglobin exhibit deviations from the regular pH dependence of exchange that is characteristic of cyanomethemoglobin. In oxyhemoglobin, the deviation from the normal exchange pattern is centered at pH 7.4 and is in the direction of increased exchange or solvent accessibility. The effect in deoxyhemogloin, while occurring at the same pH and being of the same order of magnitude, is in the opposite direction, thus suggesting a pH-induced conformational transition leading to a less accessible structure. The width of these pH-induced deviations in solvent accessibility is approximately 1 pH unit in both cases. We propose a model in which specific interactions between charged groups in both froms of ferrohemoglobin account for these deviations.

Cyanides↗
PubMed2026

Dual solvent cavities and hydrogen-bond networks define the chromophore environment in a far-red/orange-sensing cyanobacteriochrome.

Cyanobacteriochromes (CBCRs) are bilin-binding photoreceptors that exhibit remarkable spectral diversity and mediate light-dependent signaling in cyanobacteria. Far-red/orange-sensing CBCRs (froCBCRs) have attracted interest because of their unusually red-shifted absorption properties, yet structural information for their illuminated states has been lacking. Here, we report the first high-resolution (1.8 Å) crystal structure of the orange-absorbing (Po) state of the froCBCR ToFrO from Tolypothrix sp. PCC 7910. The structure reveals a compact, cyclic bilin configuration and water-mediated hydrogen-bonding networks within two solvent-accessible cavities. Within the GAF domain, the D-ring remains nearly perpendicular to the planar A-to-C ring system through interactions involving a flexible loop region. Comparative analyses of cryogenic synchrotron and room-temperature X-ray free-electron laser (XFEL) structures, together with molecular dynamics (MD) simulations, revealed alternative Met636 conformations associated with dynamic water exchange through the solvent-accessible cavity. Site-directed mutagenesis of cavity-lining and water-interacting residues resulted in modest spectral shifts. By contrast, mutations of two Trp residues, participating in π-π stacking with the D-ring and likely imposing a steric constraint near the A-ring, resulted in substantial blue and red shifts in the dark and illuminated states, respectively. Together with the observed chromophore geometry, these findings indicate that the spectral properties of ToFrO are governed by chromophore conformation and its direct interaction with surrounding residues through hydrogen-bonding, electrostatic, and π-π interactions. These results further suggest that cavity-mediated solvent organization contributes to stabilizing the local structural environment surrounding the chromophore and adjacent protein backbone. Collectively, these findings elucidate the structural basis for photoconversion and spectral tuning in froCBCRs.

Cyanobacteria↗
PubMed2025

DescribePROT Database of Residue-Level Protein Structure and Function Annotations.

DescribePROT is a freely available online database of structural and functional descriptors of proteins at the amino acid level. It provides access to 13 diverse descriptors that include sequence conservation, putative secondary structure, solvent accessibility, intrinsic disorder, and signal peptides, and putative annotations of residues that interact with proteins, peptides and nucleic acids. These data can be used to elucidate protein functions, to support efforts to develop therapeutics, and to develop and evaluate future predictors of protein structure and function. DescribePROT includes 7.8 billion predictions for 1.4 million proteins from 83 complete proteomes of popular model organisms. This information can be downloaded at multiple levels of scope (entire database, specific organisms, and individual proteins) and can be interacted with using a graphical interface that simultaneously displays data on multiple descriptors. We describe the contents of this resource, provide directions on how to use its interface, and offer instructions on how to obtain and interact with the underlying data. Moreover, we briefly discuss plans for a future expansion of this database. DescribePROT is available at http://biomine.cs.vcu.edu/servers/DESCRIBEPROT/ .

Databases, Protein↗
PubMed2025

AlphaFold2, SPINE-X, and Seder on Four Hard CASP Targets.

We analyzed four cases from the CASP15 experiment with low prediction accuracy and compared AlphaFold2, SPINE-X, and Seder on these cases. We find that overall, AlphaFold2 performs better than SPINE-X in predicting secondary structure (SS) and solvent accessible surface area (ASA). For some cases, SPINE-X better predicts sheet and coil regions. We also find that AlphaFold2 is better than Seder in selecting the best matching tertiary structure model for one case and is worse in another case. For two cases Alphafold2 and Seder selected the same models. From the cases presented here, it appears that AlphaFold2 predicts more compact structures than the native one. We find that while, as widely reported, AlphaFold2 significantly improved protein tertiary structure prediction, there are cases, such as the four presented here, for which the tertiary structure prediction could still be significantly enhanced. The source code, license, and documentation for SPINE-X and Seder are available from Research and Information Systems, LLC at http://mamiris.com .

Software↗
PubMed2026

In silico identification of DNMT1 inhibitors from the PlantCyc database through computational approach to assess the anti-cancer potential of nutraceutical compounds in breast cancer.

Breast cancer accounts for a disproportionate share of global cancer-related deaths, with 670,000 fatalities and 2.3 million new diagnoses recorded in women during 2022 alone. Existing treatment modalities carry considerable toxicity burdens, and resistance to available agents remains an unresolved clinical problem. DNA methyltransferase 1 (DNMT1), the enzyme chiefly responsible for maintaining genome-wide methylation patterns during DNA replication, has been mapped out as a high-value target in breast cancer because its dysregulation silences tumour suppressor genes through promoter hypermethylation. The present work involves hierarchical in silico workflow to screen 4549 plant-derived compounds from the PlantCyc database (v16.0.3) against the human DNMT1 catalytic domain (PDB ID: 4WXX). Ten top-scoring compounds were taken forward for molecular docking via AutoDock Vina; Quercetin and Kaempferol both recorded the highest binding affinities at -9.5 kcal/mol, Wogonin (-9.3 kcal/mol) and Xanthohumol (-8.1 kcal/mol) also emerged as strong binders. Pharmacokinetic evaluation using ADMET-AI confirmed that all 10 compounds met Lipinski's rule of five, with human intestinal absorption values at or above 0.98. Wogonin and Xanthohumol were selected for a 100 ns all-atom molecular dynamics (MD) simulation in GROMACS due to their well-rounded ADMET profiles and limited existing data on their specific interactions with DNMT1 in breast cancer. Across all measured trajectory metrics, backbone RMSD, residue fluctuation, radius of gyration, solvent-accessible surface area, and intermolecular hydrogen bond count, Wogonin formed a more stable, compact complex. These findings suggest that Wogonin and Xanthohumol are non-toxic nutraceutical candidates suitable for DNMT1 targeted epigenetic therapy, with computational foundation strong enough to facilitate future in vitro and in vivo validation work.

Humans↗
PubMed1976

Acid proteases from species of Mucor. IV. Hydrogen-tritium exchange of Mucor miehei protease.

The kinetics of hydrogen-tritium exchange were studied in the range pH-3 for both the fully and partially tritiated protein. Exchange constants for an intermediate class and slow class of hydrogens were determined and found to give a parabolic curve characteristic of acid and base catalysis about the observed pHmin of 4.03. The anomalous rate retardation on the acid portion of the curve was attributed to electrostatic interactions which could be evaluated quantitatively from the titration data. Partial tritation and pH cross-over experiments indicated that the rank order was pH-independent thus eliminating the possiblitity of a major conformational change. Consequently, the data are most likely explicable in terms of restricted solvent accessibility.

Hydrogen-Ion Concentration↗
PubMed1977

Nuclear-magnetic-resonance study of the histidine residues of S-peptide and S-protein and kinetics of 1H-2H exchange of ribonuclease A.

1H NMR spectroscopy at 100 MHz was used to determine the first-order rate constants for the 1H-2H exchange of the H-2 histidine resonances of RNase-A in 2H2O at 35 degrees C and pH meter readings of 7, 9, 10 and 10.5. Prolonged exposure in 2H2O at 35 degrees C and pH meter reading 11 caused irreversible denaturation of RN-ase-A. The rate constants at pH 7 and 9 agreed reasonably well with those obtained in 1H-3H exchange experiments by Ohe, J., Matsuo, H., Sakiyama, F. and Narita, K. [J. Biochem, (Tokyo) 75, 1197-1200 (1974)]. The rate data obtained by various authors is summarised and the reasons for the poor agreement between the data is discussed. The first-order rate constant for the exchange of His-48 increases rapidly from near zero at pH 9 (due to its inaccessibility to solvent) with increase of pH to 10.5 The corresponding values for His-119 show a decrease and those for His-12 a small increase over the same pH range. These changes are attributed to a conformational change in the hinge region of RNase-A (probably due to the titration of Tyr-25) which allows His-48 to become accessible to solvent. 1H NMR spectra of S-protein and S-peptide, and of material partially deuterated at the C-2 positions of the histidine residues confirm the reassignment of the histidine resonances of RNase-A [Bradbury, J. H. & Teh, J. S. (1975) Chem. Commun., 936-937]. The chemical shifts of the C-2 and C-4 protons of histidine-12 of S-peptide are followed as a function of pH and a pK' value of 6.75 is obtained. The reassignment of the three C-2 histidine resonances of S-protein is confirmed by partial deuteration studies. The pK' values obtained from titration of the H-2 resonances of His-48, His-105 and His-119 are 5.3, 6.5 and 6.0, respectively. The S-protein is less stable to acid than RNase-A since the former, but not the latter, shows evidence of reversible denaturation at pH 3 and 26 degrees C. His-48 in S-protein titrates normally and has a lower pK than in RN-ase-A probably because of the absence of Asp-14, which in RN-ase-A forms a a hydrogen bond with His-48 and causes it to be inaccessible to solvent, at pH values below 9.

Deuterium↗
PubMed1976

Effect of temperature on tryptophan fluorescence of beta-lactoglobulin B.

The effect of heat on the conformation of bovine beta-lactoglobulin has been studied using intrinsic fluorescence spectroscopy. Changes in the intensity, wave-length of maximum emission and emission peak width at half height of tryptophan fluorescence over the range 15-90 degrees C at pH 6.4-6.5 has allowed the environments of the two tryptophans in the molecule to be discriminated. At 20 degrees C both tryptophans are in hydrophobic environments. As the temperature is raised the conformation changes such that at about 50 degrees C one of the tryptophans is transferred to a more polar environment accessible to solvent. Conformational changes appear to be reversible if the protein is cooled to 20 degrees C after heat treatments up to 70 degrees C. Above 70 degrees C the second tryptophan residue becomes exposed to solvent. Complete exposure of one residue occurs at 80 degrees C while the other is still partially buried even at 90 degrees C. When the protein is then cooled to 20 degrees C the conformational changes appear to be irreversible with only one tryptophan residue returning to the hydrophobic interior of the molecule.

Animals↗
PubMed1977

Structural studies by proton magnetic relaxation of stereochemical probes. II. Allosteric effects in human methaemoglobin.

The haem-iron accessibility to solvent molecules in human aquomet- and fluoromethaemoglobin was studied by the magnetic relaxation of protons from a stereochemical probe (methanol in deuterated solutions) in its dependence on allosteric effects induced by inositol hexaphosphate and pH between 5.5 and 8.5. The exchange of methanol with bulk solvent was observed only when inositol hexaphosphate was bound to aquomethaemoglobin, which is consistent with a widening of the haemcrevice compared to the conformation in the absence of inositol hexaphosphate. An increase in alkalinity in the physiological range of the Bohr effect results in a gradual impedence of the solvent dynamics inside the haem-pocket. The fast-relaxation phase of methyl protons indicates that a large number of methanol molecules are under the strong influence of the protein; this effect is considerably smaller with inositol hexaphosphate bound to aquomethaemoglobin. The hypothesis which implies a proton from the coordinated water molecule is responsible for the observed relaxation rates has been critically discussed. The model with a water molecule exchanging between a position next to the sixth-ligand site of the haem-iron and the bulk solvent is further substantiated experimentally. This model has been found to be the simplest and most self consistent in the interpretation of all these proton magnetic relaxation data.

Allosteric Regulation↗
PubMed1977

Interpretation of thermal perturbation spectra of proteins.

The thermal perturbation difference spectrum of reduced lysozyme has a long wave length extremum at 304 nm at pH 6.15 and a very small extremum at 306 nm at pH 1.5. These results differ from those of Leach & Smith (1972), which showed an extremum at 293 nm, the same as for model tryptophyl compounds. Our result may arise from a conformational difference between the two sample temperatures. The interpretation of thermal perturbation spectra of proteins is discussed. Contributions from thermally induced concentration differences, buried chromophores, and chromophores in crevices are considered in the interpretation of the thermal perturbation spectrum of bovine serum albumin. It is suggested that chromophores in pauci-aqueous crevices may appear buried toward thermal perturbation spectroscopy but accessible toward solvent perturbation and chemical reagents.

Animals↗
PubMed1978

A spectral probe near the subunit catalytic site of glutamine synthetase from Escherichia coli. Reduced pyridoxal 5'-phosphate.enzyme complexes.

In order to label phosphate binding sites, unadenylylated glutamine synthetase from Escherichia coli has been pyridoxylated by reacting the enzyme with pyridoxal 5'-phosphate followed by reduction of the Schiff base with NaBH4. A complete loss in Mg2+-supported activity is associated with the incorporation of 3 eq of pyridoxal-P/subunit of the dodecamer. At this extent of modification, however, the pyridoxylated enzyme exhibits substantial Mn2+-supported activity (with increased Km values for ATP and ADP). The sites of pyridoxylation appear to have equal affinities for pyridoxal-P and to be at the enzyme surface, freely accessible to solvent. At least one of the three covalently bound pyridoxamine 5'-phosphate groups is near the subunit catalytic site and acts as a spectral probe for the interactions of the manganese.enzyme with substrates. A spectral perturbation of covalently attached pyridoxamine-P groups is caused also by specific divalent cations (Mn2+, Mg2+ or Ca2+) binding at the subunit catalytic site (but not while binding to the subunit high affinity, activating Me2+ site). In addition, the feedback inhibitors, AMP, CTP, L-tryptophan, L-alanine, and carbamyl phosphate, perturb protein-bound pyridoxamine-P groups. The spectral perturbations produced by substrate and inhibitor binding are pH-dependent and different in magnitude and maximum wavelength. Adenylylation sites are not major sites of pyridoxylation.

Binding Sites↗
PubMed1977

Circular dichroic and perturbation spectra of aromatic chromophores in rabbit tropomyosin. Topography of tyrosine residues.

1. Difference spectra of tryosyl residues obtained on denaturation of tropomycosin with urea or guanidinium chloride indicate that strong hydrophobic environments exist in the native coiled-coil state. 2. Solvent perturbation difference spectra indicate that tyrosyl residues are partially accessible to the solvent. The accessiblity decreases with increasing size of the solvent molecules. 3. Spectral pH titration of tyrosyl residues cannot provide information on the tyrosyl accessibility because conformational change accompanies the increase in pH. 4. Circular dichroism of tyrosyl and phenylalanyl residues is consistent with the effect of imposed conformational rigidity on the partially asymmetrical vibrational fine structure of the 1Lb absorption band of phenyl and benzyl chromophores; the effect is reduced by 70% on unfolding of tropomyosin.

Animals↗
PubMed1976

Fluorimetric studies of tryptophyl exposure in concanavalin A.

Studies of the iodide ion quenching of the intrinsic fluorescence of Concanavalin A indicate that 50% of the tryptophyl fluorescence originates from exposed residues. This agrees with the X-ray crystallographic determination that two of the four tryptophan residues in a Concanavalin A monomer are on the surface. Previous studies have indicated that conformational changes induced by sugar binding alter the environment of aromatic residues. The present investigation finds that neither the specific binding of alpha-methyl-D-mannoside nor alteration of the Concanavalin A quaternary structure changes the number or accessibility of the solvent-exposed tryptophan residues. It therefore appears that the major conformational transitions in Concanavalin A do not affect steric access to the surface tryptophans and the effects previously observed may be ascribed to structurally internal tryptophan residues.

Binding Sites↗
PubMed1977

A proton magnetic relaxation study of ferric myoglobin and haemoglobin in water/ethanediol solutions.

Structural alterations of the haem vicinity of the high-spin derivatives of bovine ferric myoglobin (metmyoglobin) and human haemoglobin and the changes of the interaction with inositol hexaphosphate induced by ethanediol were monitored by solvent-proton magnetic relaxation. On addition of ethanediol up to 60% the fluoromet derivatives exhibit a gradual increase in the accessibility of the haem for the molecules from the solvent. In aquomethaemoglobin solutions with more than 25% ethanediol there is no unique explanation of proton magnetic relaxation. Ethanediol enhances the binding of inositol hexaphosphate to methaemoglobin, but the structural consequences of this binding on the haem-pockets seem to be diminished. The mechanisms of the observed structural and functional alterations of myoglobin as well as haemoglobin tetramer are discussed here.

Animals↗
PubMed1978

Influence of phosphate ligands in abolishing the conformational difference between ribonuclease A and its acid-denatured derivative.

The initial structural alteration of RNAase A due to acid denaturation (0.5 N HCl, 30 degrees C) that accompanies deamidation (without altering enzymic activity) has been dectected by spectrophotometric titration, fluorescence and ORD/CD measurements. It is shown that acid treated RNAase A has an altered conformation at neutral pH, 25 degrees C. This is characterized by the increased accessibility of buried tyrosine residue(s) towards the solvent. The most altered conformation of RNAase A is found in the 10 h acid-treated derivative. This has about 1.5 additional exposed tyrosine residues and a lesser amount of secondary structure than RNAase A. All three methods (titration, fluorescence and CD) established that the structural transition of RNAase A is biphasic. The first phase occurs within 1 h and the resulting subtle conformational change is constant up to 7 h. Following this, after the release of 0.55 mol of ammonia, the major conformational change begins. The altered conformation of the acid-denatured RNAase A could be reversed completely to the native state through a conformational change induced by substrate analogs like 2'- or 3'-CMP. Thus the monodeamidated derivative isolated from the acid-denatured RNAase A by phosphate is very similar to RNAase A in over-all conformation. The results suggest the possibility of flexibility in the RNAase A molecule that does not affect its catalytic activity, as probed through the tyrosine residues.

Amides↗
PubMedDate not supplied

[Fibrinogen and fibrin monomer conformation changes dependent of pH magnitude].

Conformational states of fibrinogen and fibrin monomer were studied by methods of differential and solvent-perturbation spectrophotometry and ultraviolet fluorescence at about neutral pH (6.5) and in the region of lower pH, 3.2 to 4.0. To prevent repolymerization of fibrin monomer at pH 6.5, urea was added in a non-denaturing concentration of 1.7 M. In the acid region specified, the immediate environment of tyrosine and tryptophan residues was found to be more polar and the accessibility to perturbants higher than at pH 6.5. Much more drastic changes of the same type occurred at pH less than 3 when denaturation of the protein takes place. The conformation of fibrinogen altered progressively upon lowering pH from 4.0 to 3.2. This acidity increase, practically, did not influence the conformation of fibrin monomer. Thus the tolerance of the latter to the appearance of the new positively changed groups seems to be comparably high. The bulk of the conformational changes subsequent upon neutralization of an acid fibrin monomer solution proceeds at a higher rate than the activation transition, i.e. the acquirement of a state of polymerization readiness by fibrin monomer molecules.

Animals↗
PubMed1977

The reactivities of tyrosine and tryptophan residues in lipid-bound cytochrome b5.

Purified cytochrome b5 from rabbit liver microsomes was bound to liposomes prepared from microsomal lipids. Tyrosyl and tryptophyl side chains of the protein were modified by water-soluble reagents and the reactivities of these amino acid residues in the liposome-bound cytochrome b5 were compared to those of the free protein. At pH 13, 80% of the tyrosines in lipid-free cytochrome b5 ionized immediately, whereas in the lipid-bound protein only 65% ionized within the first minute. In contrast, acetylation with acetylimidazole resulted in the conversion of all 5 tyrosine groups of lipid-free as well as lipid-bound cytochrome b5 into O-acetylated derivatives, which upon treatment with hydroxylamine were completely deacetylated. Reaction with N-bromosuccinimide revealed that only 60% of the 4 tryptophan residues present in cytochrome b5 were accessible to the reagent in the lipid-bound protein, although all tryptophans could be modified in lipid free cytochrome b5. It was concluded that the two tyrosines in the region linking the protein to the membrane are not shielded by lipid bilayer but that of the three tryptophans in the same region one is completely buried in the membrane, whereas the remaining two tryptophans may be both partly exposed to the solvent or alternatively, one may be partially and the other completely exposed.

Animals↗