Biomedical subjects

S G Jacchieri

Publications and source records attributed to S G Jacchieri.

8 recordsLinked to original sources

PubMed2001

Stepwise assembling of polypeptide chain energy distributions.

The principles and application of conformational analysis software that makes use of a new algorithm are described. It is known that the existence of a local energy minimum in the energy landscape is in general related to the clustering of polypeptide chain conformations near that energy value or, in other words, to a high density of states. A criterion based on this principle is part of an algorithm employed to select subsets of polypeptide chain conformations in broad energy ranges. Chain fragments belonging to these subsets are then combined to build larger polypeptide chains and the corresponding energy distributions. The functionality of the various operations employed in the process is described and the FORTRAN 77 source code that defines the algorithm is listed. The methodology is illustrated with a calculation involving three chain fragments belonging to the cellular prion protein (PrP(C)).

Algorithms↗

PubMed2000

Mining combinatorial data in protein sequences and structures.

Combinatorial searches of structural and physical chemical properties involving the components of libraries of dipeptide, tripeptide and tetra peptide fragments were carried out in the Protein Data Bank and the SwissProt databases. The properties investigated are structural propensities, co localization of peptide fragments in protein sequences, interactions between peptide fragments in close structural proximity and the participation of physical chemical profiles in the distribution of structural motifs among peptide fragments. The results obtained for each combinatorial search in the study are classified according to the structural motifs alpha-helix, beta-sheet, reverse turn I and reverse turn II. The application of combinatorial data mined in protein databases to the design of new peptide libraries is discussed. The present findings have implications for the study of protein structure which are also discussed.

Algorithms↗

PubMed1998

Study of alpha-helix to beta-strand to beta-sheet transitions in amyloid: the role of segregated hydrophobic beta-strands.

A conformational analysis including three polypeptide chains known to be amyloidogenic and neurotoxic has shown the occurrence of low probability hydrophobic beta-strands stabilized by intramolecular interactions. It is argued that by engaging in non-bonded and hydrophobic interactions these beta-strands seed the assembly of beta-sheets in amyloid fibrils following a non-cooperative mechanism dissimilar to beta-sheet folding in proteins. Molecular models of amyloid fibrils formed by such beta-strand templates were built. It is shown that the parallel alignment of beta-strands creates an extensive hydrophobic surface whereas the antiparallel alignment causes the formation of hydrophobic and hydrophilic aggregates. A comparison with experimental data and previous calculations is established.

Amino Acid Sequence↗

PubMed1998

Comparative conformational analysis of peptide libraries.

Six computer-based combinatorial libraries, including tetrapeptide sequences (generated with five amino acids) and conformations (generated with five main chain and three side chain rotamers), were obtained and sequence-conformation probabilities were calculated with a molecular and statistical mechanics procedure. The structural motifs alpha-helix, beta-sheet, 3(10)-helix, reverse turn I and gamma-turn were focused in these calculations. It is shown that sequence-conformation-probability surfaces provide a broad view of structural changes accompanying changes in sequence. Numerical indices are defined to enable comparisons between frequencies of occurrence of these structural motifs in peptide libraries and in a database of low sequence identity protein structures. Fine details of sequence-conformation-probability surfaces show the effect of point mutations. Broad comparisons between different regions of these surfaces indicate how to select the occurrence of structural motifs in the combinatorial synthesis of peptide chains.

Algorithms↗

PubMed1998

A comparative conformational analysis of thimet oligopeptidase (EC 3.4.24.15) substrates.

The specificity of thimet oligopeptidase (EC 3.4.24.15) (TOP 24.15) does not agree with theoretical models devised to explain the specificity characteristic of peptidases toward certain sequences of amino acid residues. According to previous studies peptide chains hydrolyzed by TOP 24.15 adopt similar main chain conformations, although with different and in some cases small probabilities of occurrence in aqueous solution. To determine specific structural features recognized by TOP 24.15, a conformational search including eight polypeptides with known susceptibilities for catalytic hydrolysis was executed and the distribution of each main chain conformation found in the search was tabulated. Two sets of main chain conformations were selected, those common to all peptides in the study and those common only to substrates of TOP 24.15. The former set is very small and includes mainly extended conformations. In contrast, the latter set is large and its conformations are coiled and exhibit sharp turns coincident with positions of hydrolysis by TOP 24.15. These results indicate a possible basis for the selectivity of TOP 24.15.

Kinetics↗

PubMed1993

Probing the influence of sequence-dependent interactions upon alpha-helix stability in alanine-based linear peptides.

The observation that short, linear alanine-based polypeptides form stable alpha-helices in aqueous solution has allowed the development of well-defined experimental systems with which to study the influence of amino acid sequence upon the stability of secondary structure. We have performed detailed conformational searches upon six alanine-based peptides in order to rationalize the observed variation in the alpha-helical stability in terms of side-chain-backbone and side-chain-side-chain interactions. Although a simple, gas-phase, potential model was used to obtain the conformational energies for these peptides, good agreement was obtained with experiment regarding their relative alpha-helical stabilities. Our calculations clearly indicate that valine, isoleucine, and phenylalanine residues should destabilize the alpha-helical conformation when included within alanine-based peptides because of energetically unfavorable side-chain-backbone interactions, which tend to result in the formation of regions of 3(10)-helix. In the case of valine, the destabilization most probably arises from entropic effects as the isopropyl side chain can assume more orientations in the 3(10)-helical form of the peptide. A detailed examination of very short-range interactions in these peptides has also indicated that an interaction, involving fewer than five consecutive residues, whose stabilizing effect reinforces that of the (i, i + 4) hydrogen bond may be the basis of the requirement for increased nucleation (sigma) and propagation parameters (s) required by Zimm-Bragg theory to predict the alpha-helical content for compounds in this class of short peptides. Our calculations complement recent work using modified Zimm-Bragg and Lifson-Roig theories of the helix-coil transition, and are consistent with molecular dynamics simulations upon linear peptides in aqueous solution.

Alanine↗

PubMed1992

Variable ranges of interactions in polypeptide conformations with a method to complement molecular modeling.

Formulations of conformational weights for helix-coil transitions can be extended to substantially more complex situations than are usually pursued. General rules for matrix multiplication that depend parametrically on the interaction ranges and numbers of rotamers of residues are presented. The orders of the matrices of statistical weights can be increased with chain length, so that an individual matrix element can represent any specified single conformation, as needed. By the appropriate choice of interaction ranges and numbers of available conformers, approximations can be introduced in which: (1) an average of the conformations of any chain segment is obtained, (2) specific residue-residue interactions are excluded, or (3) the conformation of a part of the chain is restricted or fixed. The method is appropriate for treating specific interactions in peptides and could be used together with available experimental information to develop models of conformational transitions. As such, the methods represent a class of calculations aimed at more rigorous calculations built around known features of a molecule. The aim is to facilitate calculations that bridge the gap between nonquantitative molecular model building and more rigorous but less directed molecular mechanics calculations. The method can directly include any desired longer range of interactions, if the interaction range is not too long to make impossible the manipulation of the requisite matrices. An outline is presented of an application to treat salt bridges in the C peptide of ribonuclease A.

Models, Molecular↗

PubMed1984

Why are there two kinds of chain in tetrameric hemoglobins?

It is shown that the mean allosteric free energy G0(34,12) measures cooperative dioxygen binding in tetrameric hemoglobins. For human hemoglobin G0(34,12) is slightly temperature enhanced between 10 and 35 degrees C. This remarkable thermal behaviour depends on the presence in Hb of two functionally non-equivalent chains. It is proposed that this made the existence of alpha 2 beta 2 hemoglobins biologically advantageous.

Allosteric Site↗