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Biomedical subjects

A V Finkelstein

Publications and source records attributed to A V Finkelstein.

At least 19 recordsLinked to original sources
PubMed1992

De novo design, synthesis and study of albebetin, a polypeptide with a predetermined three-dimensional structure. Probing the structure at the nanogram level.

The de novo polypeptide named albebetin was designed to form the tertiary fold that has not yet been observed in natural proteins. The design was based on the molecular theory of protein structures. The gene coding for this polypeptide was chemically synthesized. For the initial characterization of a protein structure, a new approach has been developed that uses only nanogram amounts of a polypeptide without its previous purification. This approach includes the biosynthesis of radiolabeled protein in a cell-free translation system with subsequent analysis of its compactness and structure by size-exclusion chromatography, urea-gradient electrophoresis and limited proteolysis. According to all tests used, albebetin has a compact stable structure.

Amino Acid Sequence↗
PubMed1992

Protein design on computers. Five new proteins: Shpilka, Grendel, Fingerclasp, Leather, and Aida.

What is the current state of the art in protein design? This question was approached in a recent two-week protein design workshop sponsored by EMBO and held at the EMBL in Heidelberg. The goals were to test available design tools and to explore new design strategies. Five novel proteins were designed: Shpilka, a sandwich of two four-stranded beta-sheets, a scaffold on which to explore variations in loop topology; Grendel, a four-helical membrane anchor, ready for fusion to water-soluble functional domains; Finger-clasp, a dimer of interdigitating beta-beta-alpha units, the simplest variant of the "handshake" structural class; Aida, an antibody binding surface intended to be specific for flavodoxin; Leather--a minimal NAD binding domain, extracted from a larger protein. Each design is available as a set of three-dimensional coordinates, the corresponding amino acid sequence and a set of analytical results. The designs are placed in the public domain for scrutiny, improvement, and possible experimental verification.

Algorithms↗
PubMed1992

Search for the stable state of a short chain in a molecular field.

A general approach is developed to search for stable structures of short chain fragments (e.g. of loops or bound oligopeptides) in a given molecular field. This molecular field is produced by the remaining part of a globule or by any other surface with a defined spatial structure. The fragment must be short enough to have no pronounced long-range interactions within itself. The method is illustrated by calculation of the 3-D structures of two loops of bovine pancreatic trypsin inhibitor (BPTI). Computations are based on a lattice model of conformational space and on strict and fast algorithms of 1-D statistical mechanics and dynamic programming (which are very similar in essence). This makes a search of oligopeptide structures only several times (and not several orders of magnitude) longer than that of a dipeptide.

Algorithms↗
PubMed1992

A new approach to the design of a sequence with the highest affinity for a molecular surface.

We describe an algorithm to design the primary structures for peptides which must have the strongest binding to a given molecular surface. This problem cannot be solved by a direct combinatorial sorting, because of an enormous number of possible primary and spatial structures. The approach to solve this problem is to describe a state of each residue by two variables: (i) amino acid type and (ii) 3-D coordinate, and to minimize binding energy over all these variables simultaneously. For short chains which have no long-range interactions within themselves, this minimization can be done easily and efficiently by dynamic programming. We also discuss the problem of how to estimate specificity of binding and how to deduce a sequence with maximal specificity for a given surface. We show that this sequence can be deduced by the same algorithm after some modification of energetic parameters.

Algorithms↗
PubMed1991

A search for the most stable folds of protein chains.

It is generally believed that it is not sensible to search for a thermodynamically stable structure of a protein because neither a molecule nor a computer can look through all the 3(100) possible (for 100 residues) chain conformations. Here we show that the use of a molecular field theory for the long-range interactions, the use of one-dimensional statistical mechanics for the short-range ones and the discovery that there are and there must be only a small discrete set of folding patterns, make it possible to examine all the variety of 'potentially stable' structures. The general approach and its application is demonstrated here by calculation of stable folds for some beta domains. The most stable of these folds correspond to the observed structures.

Chemical Phenomena↗
PubMed1991

Rate of beta-structure formation in polypeptides.

An explanation is suggested for why a marginally stable beta-structure folds extremely slowly; it is predicted that even a small increase in stability drastically accelerates beta-folding. According to the theory, this folding is a first-order phase transition, and the rate-limiting step is nucleation. The rate-determining "nucleus" (transition state) is the smallest beta-sheet that is sufficiently large to provide an overall free energy reduction during subsequent folding. If the stability of the beta-structure is low, the nucleus is large and possesses a high free energy due to having a large perimeter. When the net stability of the final beta-structure increases (due to either an increase of the beta-sheet stability or a decrease in stability of the competing structures, e.g., alpha-helices), the size and energy of a nucleus decrease and the rate of folding increases exponentially. This must result in a fast folding of polypeptides enriched by beta-forming residues (e.g., protein chains). The theory is developed for intramolecular beta-structure, but it can also explain the overall features of intermolecular beta-folding; it is applicable both to antiparallel and parallel beta-sheets. The difference in folding of beta-sheets, alpha-helices, and proteins is discussed.

Kinetics↗
PubMed1991

Physical reasons for secondary structure stability: alpha-helices in short peptides.

It was recently found that some short peptides (including C- and S-peptide fragments of RNase A) can have considerable helicity in solution, which was considered to be surprising. Does the observed helicity require a new explanation, or is it consistent with previous understanding? In this work we show that this helicity is consistent with the physical theory of secondary structure based on an extension of the conventional Zimm-Bragg model. Without any special modifications, this theory explains reasonably well almost all the experimentally observed dependencies of helicity on pH, temperature, and amino acid replacements. We conclude that the observed "general level" of helicity of C- and S-peptides (5-30% at room temperature and 10-50% near 0 degrees C) is "normal" for short peptides consisting mainly of helix-forming and helix-indifferent residues. The helicity is modified by a multitude of weak specific side chain interactions, many of which are taken into account by the present theory; some discrepancies between the theory and experiment can be explained by weak side-chain-side chain interactions that were neglected. A reasonable coincidence of the theory with experiment suggests that it had been used to investigate the role of local interactions in the formation of alpha-helical "embryos" in unfolded protein chains.

Amino Acid Sequence↗
PubMed1989

Theory of cooperative transitions in protein molecules. I. Why denaturation of globular protein is a first-order phase transition.

A theory of equilibrium denaturation of proteins is suggested. According to this theory, a cornerstone of protein denaturation is disruption of tight packing of side chains in protein core. Investigation of this disruption is the object of this paper. It is shown that this disruption is an "all-or-none" transition (independent of how compact is the denatured state of a protein and independent of the protein-solvent interactions) because expansion of a globule must exceed some threshold to release rotational isomerization of side chains. Smaller expansion cannot produce entropy compensation of nonbonded energy loss; this is the origin of a free-energy barrier (transition state) between the native and denatured states. The density of the transition state is so high that the solvent cannot penetrate into protein in this state. The results obtained in this paper make it possible to present in the following paper a general phase diagram of protein molecule in solution.

Kinetics↗
PubMed1989

Theory of cooperative transitions in protein molecules. II. Phase diagram for a protein molecule in solution.

The thermodynamically stable states of denatured protein in solution are investigated. These states are distinguished from the native state by the absence of tight packing of side chains while the compactness of denatured protein may vary within a wide region. The following regimes are outlined: 1. the "wet" molten globule, i.e., the compact state with pores occupied by solvent; 2. the swollen globule ("wet," of course); and 3. the coil. The "dry" molten globule, when solvent does not penetrate inside the protein, is excluded for all experimental conditions. All the transitions within the denatured globule state are gradual while the denatured globule-coil phase transition is a second order one. The conditions of protein denaturation as well as conditions of transitions and crossovers within the denatured state are outlined.

Chemical Phenomena↗
PubMed1989

Prediction of protein secondary structure based on physical theory. Histones.

Secondary structures of histones H1, H2A, H2B, H3, H4 and H5 have been calculated by the computer program ALB based on a molecular theory of protein secondary structure. The predicted secondary structures of all histones are predominantly alpha-helical. The calculated secondary structure of linker histones H1 and H5 is close to that previously obtained from two-dimensional NMR data. For each of the core histones (H2A, H2B, H3, H4) one long alpha-helix and several short ones have been predicted. These long helices can be identified with rods in the low-resolution electron density map.

Computer Simulation↗
PubMed1988

General architecture of the alpha-helical globule.

A model is presented for the arrangement of alpha-helices in globular proteins. In the model, helices are placed on certain ribs of "quasi-spherical" polyhedra. The polyhedra are chosen so as to allow the close packing of helices around a hydrophobic core and to stress the collective interactions of the individual helices. The model predicts a small set of stable architectures for alpha-helices in globular proteins and describes the geometries of the helix packings. Some of the predicted helix arrangements have already been observed in known protein structures; others are new. An analysis of the three-dimensional structures of all proteins for which co-ordinates are available shows that the model closely approximates the arrangements and packing of helices actually observed. The average deviations of the real helix axes from those in the model polyhedra is +/- 20 degrees in orientation and +/- 2 A in position (1 A = 0.1 nm). We also show that for proteins that are not homologous, but whose helix arrangements are described by the same polyhedron, the root-mean-square difference in the position of the C alpha atoms in the helices is 1.6 to 3.0 A.

Animals↗
PubMed1987

Prediction of secondary structure, spatial organization and distribution of antigenic determinants for hepatitis A virus proteins.

On the basis of the secondary structure calculations from the known amino acid sequence we came to the conclusion that hepatitis A virus capsid proteins have the typical antiparallel beta-sheet bilayer structure. The predicted secondary structure of the HAV proteins can be well aligned with those of the poliovirus (type 1 Mahoney) and human rhinovirus (type 14). It enabled us to use the X-ray structure of the PV-1M and HRV-14 proteins as a template and then, firstly, to localize the positions of alpha and beta regions in the architecture of the HAV protein molecules and, secondly, to discover the amino acid homologies of the secondary structure regions aligned. The obtained model of the three-dimensional structure for HAV proteins helped us to indicate the exposed regions of the polypeptide chains and to pinpoint the potential neutralizing antigenic sites.

Amino Acid Sequence↗
PubMed1985

Structural model for interferons.

Secondary structures of leucocyte alpha 1- and alpha 2-interferons and of fibroblast beta-interferon are calculated using the molecular theory of protein secondary structures. The common secondary structure calculated for alpha- and beta-interferons is used to predict the three-dimensional structures of fragments 1-110 and 111-166 of the chains (which are supposed to be quasi-independent domains). The predicted structure of the active domain I (1-110) is an 'up-and-down' tetrahelical complex (in which the second helix is shorter than the others and can be absent in alpha 1-interferon) similar to the mirror image of myohaemoerythrin. The predicted structure of domain II (111-166) is either a three-stranded beta-sheet screened from one side by two alpha-helices or a three-helical complex (similar to that in the N-domain of papain), the first structure being more consistent with the circular dichroism data of alpha-interferon and its C-end fragment.

Circular Dichroism↗