Biomedical subjects

O V Galzitskaya

Publications and source records attributed to O V Galzitskaya.

9 recordsLinked to original sources

PubMed2001

Folding nuclei in proteins.

When a protein folds or unfolds, it passes through many half-folded microstates. Only a few of them can accumulate and be seen experimentally, and this happens only when the folding (or unfolding) occurs far from the point of thermodynamic equilibrium between the native and denatured states. The universal features of folding, though, are observed just close to the equilibrium point. Here the 'two-state' transition proceeds without any accumulation of metastable intermediates, and only the transition state ('folding nucleus') is outlined by its key influence on the folding-unfolding kinetics. Our aim is to review recent experimental and theoretical studies of the folding nuclei.

Kinetics↗

PubMed2000

Optimal region of average side-chain entropy for fast protein folding.

Search and study the general principles that govern kinetics and thermodynamics of protein folding generates new insight into the factors that control this process. Here, we demonstrate based on the known experimental data and using theoretical modeling of protein folding that side-chain entropy is one of the general determinants of protein folding. We show for proteins belonging to the same structural family that there exists an optimal relationship between the average side-chain entropy and the average number of contacts per residue for fast folding kinetics. Analysis of side-chain entropy for proteins that fold without additional agents demonstrates that there exists an optimal region of average side-chain entropy for fast folding. Deviation of the average side-chain entropy from the optimal region results in an anomalous protein folding process (prions, alpha-lytic protease, subtilisin, some DNA-binding proteins). Proteins with high or low side-chain entropy would have extended unfolded regions and would require some additional agents for complete folding. Such proteins are common in nature, and their structure properties have biological importance.

Entropy↗

PubMed2000

Folding nuclei in 3D protein structures.

This paper presents and analyzes the results of several new approaches to the problem of finding the folding nucleus in a given 3D protein structure. Firstly, we show that the participation of residues in the hydrophobic core and the secondary structure of native protein has a rather modest correlation with the experimentally found phi values characterizing the participation of residues in the folding nuclei. Then we tried to find the nuclei as the free energy saddle points on the network of the folding/unfolding pathways using the branch-and-bound technique and dynamic programming. We also attempted to estimate the phi values from solving of kinetic equations for the network of protein folding/unfolding pathways. These approaches give a better correlation with experiment, and the estimated folding time is consistent with the experimentally observed rapid folding of small proteins.

Computer Simulation↗

PubMed1999

A theoretical search for folding/unfolding nuclei in three-dimensional protein structures.

When a protein folds or unfolds, it has to pass through many half-folded microstates. Only a few of them can be seen experimentally. In a two-state transition proceeding with no accumulation of metastable intermediates [Fersht, A. R. (1995) Curr. Opin. Struct. Biol. 5, 79-84], only the semifolded microstates corresponding to the transition state can be outlined; they influence the folding/unfolding kinetics. Our aim is to calculate them, provided the three-dimensional protein structure is given. The presented approach follows from the capillarity theory of protein folding and unfolding [Wolynes, P. G. (1997) Proc. Natl. Acad. Sci. USA 94, 6170-6175]. The approach is based on a search for free-energy saddle point(s) on a network of protein unfolding pathways. Under some approximations, this search is rapidly performed by dynamic programming and, despite its relative simplicity, gives a good correlation with experiment. The computed folding nuclei look like ensembles of those compact and closely packed parts of the three-dimensional native folds that contain a small number of disordered protruding loops. Their estimated free energy is consistent with the rapid (within seconds) folding and unfolding of small proteins at the point of thermodynamic equilibrium between the native fold and the coil.

Protein Conformation↗

PubMed1998

Hyperphosphorylation induces structural modification of tau-protein.

The effect of hyperphosphorylation on the structural properties and conformational stability of bovine tau-protein was studied by means of circular dichroism and fluorescence lifetime techniques. Normal protein contains unusual secondary structure elements: extended left-handed helices. The structure of this protein was assumed to be of a 'tadpole' type - a globular C-terminal part with a long and rigid tail included in the extended left-handed helix. Either a decrease or an increase of pH induced only minor changes of the normal tau-protein surface. Hyperphosphorylation affected the extended part of the protein molecule; the decrease of pH in this case induced considerable structural rearrangements, and the conformation of the C-terminal part of the protein molecule was transformed into a molten globule-like state.

Animals↗

PubMed1997

Geometrical factor and physical reasons for its influence on the kinetic and thermodynamic properties of RNA-like heteropolymers.

BACKGROUND: It has been shown that not only the primary sequence but also the geometry of the native conformation influences the kinetic and thermodynamic properties of a protein-like model. The purpose of this paper is to elucidate the geometrical factor, which affects the kinetic and thermodynamic properties of RNA-like heteropolymers, and physical reasons for this phenomenon. RESULTS: It is shown that increasing the strength of long-range contacts can accelerate the finding of the native secondary structure for RNA-like heteropolymers. Decreasing the strength of long-range contacts results in deceleration of this process. The physical reason for this phenomenon is the increase in the average energy of non-native structures and, as a consequence, the increase (in absolute value) of the relative value of native energy from strengthening long-range contacts under constant energy of the native state. Statistical analysis of natural RNAs has shown that the mean stability of helices formed by the pairing of regions that are remote along the chain prevails over the mean stability of helices formed by regions that are close along the chain. CONCLUSIONS: The kinetics simulations suggest that the folding of the RNA secondary structure depends on the structural factors of the native state. One of these factors accelerating large RNA folding is the existence of strong long-range helices in the native secondary structure.

Animals↗

PubMed1997

Roughness of the globular protein surface: analysis of high resolution X-ray data.

In an earlier publication [Serdyuk, I.N. et al., Biofizika, in press, 1997] we demonstrated that the asymmetry extent of globular proteins does not change with increasing their sizes, and the observed nontrivial dependence of the protein accessible surface area on the molecular mass [Miller, S., J. Mol. Biol. 196:641-656, 1987] (A(s) - M dependence) is a reflection of the protein surface relief peculiarities. To clarify these peculiarities, an analysis of the molecular surface on the basis of high-resolution x-ray data has been done for 25 globular proteins not containing prosthetic groups. The procedure was based on studying the dependence of the minimal number (N) of probe bodies (here cubes) covering the entire protein surface, both on their size (N - R dependence) and on the value of dry protein volume (N - V dependence). Two levels of protein surface organization have been detected by molecular surface analysis. On the micro scale (2-7 A), the surface is characterized by a D = 2.1 fractal dimension which is intrinsic to surfaces with weak deformations and reflects the local atomic group packing. On the macro scale, large-scale surface defects are revealed that are interpreted as the result of secondary structure elements packing. A simple model of protein surface representation reflecting large-scale irregularities has been proposed.

Fractals↗

PubMed1995

Folding of chains with random and edited sequences: similarities and differences.

We have investigated the process of protein folding by Monte-Carlo simulation of folding occurring in a simple 3D lattice model of a protein globule. We have found the range of 'optimal' temperatures where the native fold is achieved by the Monte-Carlo process much faster than that by exhaustive sorting of all the chain folds. The 'optimal' temperatures are essentially the same for different random and 'edited' sequences (for the latter, the native fold energy is separated by a considerable gap from the energies of other low-energy folds; for random sequences, this gap is negligible). At the 'optimal' temperatures, the 'edited' chains attain their native fold faster than the random ones. However, the essence is that the native folds of 'edited' chains are thermodynamically stable at temperatures optimal for fast folding, while the native folds of random chains are unstable at the temperatures optimal for fast folding; also, at low temperatures where the native folds of random chains are stable, folding kinetics is very slow. Consequently, stable native folds are formed slowly by random sequences and rapidly by the 'edited' ones.

Computer Simulation↗

PubMedDate not supplied

[The interaction of the GroEL chaperone with early kinetic intermediates of renaturing proteins inhibits the formation of their native structure].

The main function of the chaperone GroEL is to prevent nonspecific association of nonnative protein chains and provide their correct folding. In the present work, the renaturation kinetics of three globular proteins (human alpha-lactalbumin, bovine carbonic anhydrase, and yeast phosphoglycerate kinase) in the presence of different molar excess of GroEL (up to 10-fold) was studied. It was shown that the formation of the native structure during the refolding of these proteins is retarded with an increase in GroEL molar excess due to the interaction of kinetic protein intermediates with the chaperone. Mg(2+)-ATP and Mg(2+)-ADP weaken this interaction and decrease the retarding effect of GroEL on the protein refolding kinetics. The theoretical modeling of protein folding in the presence of GroEL showed that the experimentally observed linear increase in the protein refolding half-time with increasing molar excess of GroEL must occur only when the protein adopts its native structure outside of GroEL (i.e. in the free state), while the refolding of the protein in the complex with GroEL is inhibited. The dissociation constants of GroEL complexed with the kinetic intermediates of the proteins studied were evaluated, and a simple mechanism of the functioning of GroEL as a molecular chaperone was proposed.

Adenosine Diphosphate↗