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We describe a new clustering program, SONHICA (Simple Optimized Non-HIerarchical Cluster Analysis), developed to analyze large data sets of molecular conformations. Unlike traditional clustering methods, SONHICA does not make use of an overall index, like a distance, to evaluate similarity between objects. Each descriptor variable is compared individually on the basis of a preset threshold value. This assures high control and sensitivity over the input variables. In addition, periodic and nonperiodic descriptors, such as dihedral angles and interatomic distances, can easily be used together. SONHICA generates clusters with the highest possible density and all pairs of objects within a cluster are similar. These features make SONHICA particularly suitable for the analysis of data sets which tend to form globular clusters. This method was applied to the analysis of a modified linear tetrapeptide, ITF1697, under investigation for its anti-ischemic properties, and a cyclic pentapeptide, BQ123, a potent antagonist of endothelin A. On the basis of the results presented here, SONHICA appears to be an interesting new tool in the field of the clustering methods applied to the analysis of molecular conformations. © 1997 John Wiley & Sons, Inc. J Comput Chem18: 1295–1311, 1997

In the absence of specific interactions, the relative attenuation of protein NMR signals due to added stable free radicals such as TEMPOL should reflect the solvent accessibility of the molecular surface. The quantitative correlation between observed attenuation and surface accessibility was investigated with a model system, i.e., the small protein bovine pancreatic trypsin inhibitor. A detailed discussion is presented on the reliability and limits of the approach, and guidelines are provided for data acquisition, treatment, and interpretation. The NMR-derived accessibilities are compared with those obtained from x-ray diffraction and molecular dynamics data. Although the time-averaged accessibilities from molecular dynamics are ideally suited to fit the NMR data, better agreement was observed between the paramagnetic attenuations of the fingerprint cross-peaks of homonuclear proton spectra and the total NH and H alpha accessibilities calculated from x-ray coordinates, than from time-averaged molecular dynamics simulations. In addition, the solvent perturbation response appears to be a promising approach for detecting the thermal conformational evolution of secondary structure elements in proteins.

The recently proposed WHIM (Weighted Holistic Invariant Molecular) approach [Todeschini,R., Lasagni, M. and Marengo, E., J. Chemometrics, 8 (1994) 263] has been applied tomolecular surfaces to derive new 3D theoretical descriptors, called MS-WHIM. To test theirreliability, a 3D QSAR study has been performed on a series of steroids, comparing the MS-WHIM description to both the original WHIM indices and CoMFA fields. The analysis of thestatistical models obtained shows that MS-WHIM descriptors provide meaningful quantitativestructure–activity correlations. Thus, the results obtained agree well with thoseachieved using CoMFA fields. The concise number of indices, the ease of their calculationand their invariance to the coordinate system make MS-WHIM an attractive tool for 3DQSAR studies.

Conformationally constrained peptidomimetics of the Lys-Pro sequence have been obtained using a new polycyclic structure. Bicyclic compounds containing a dioxopiperazine-thiazolidine fused ring have been synthesised starting from N-lysyl-4-ethoxycarbonylthiazolidine-2-carboxylic acid. The carboxyl group in either position 2 or 4 of the thiazolidine ring was reacted with the N-terminal amino group, giving different regioisomers. NMR and computer modelling were used to study the configuration of isomers and the lysine side-chain orientation with respect to the pseudoproline ring.

Two basic biological functions have been investigated: cell proliferation and metabolic processes. A culture of human lymphocytes was subjected to irradiation with light of various doses and wavelengths. Spontaneous lymphocyte proliferation was studied, as well as proliferation in response to mitogenic stimulation by phytohemagglutinin (PHA). A parallel investigation has been devoted to metabolic energy supplying process, in particular to enzyme (myosin ATPase) reactivation. Common features and mechanisms underlying this complex phenomenological response are discussed.© (1993) COPYRIGHT SPIE--The International Society for Optical Engineering. Downloading of the abstract is permitted for personal use only.

Tuftsin, a natural linear tetrapeptide (Thr-Lys-Pro-Arg) of potential antitumor activity, has been studied in DMSO-d6 solution by 2D NMR spectroscopy. 1H and 13C spectra show the presence of two families of conformations characterized by a trans or cis Lys-Pro bond, respectively. The family of conformers containing the cis peptide bond is a mixture of extended structures as expected for a short linear peptide. On the contrary, the trans isomer appears to be a rigid, folded conformer, as indicated by crucial NOEs and by the exceptionally low temperature coefficient of Arg NH. Analysis of the solution data by means of energy calculations leads to a unique structure, characterized by a Lys-Pro inverse gamma-turn.

A method for the quantitative determination of interproton distances from H-1 NOE relayed heteronuclear correlation is presented. Model compounds are investigated. Accurate distances are obtained if all the factors affecting such distance measurements, such as the local mobility and the presence of strong coupling in heteronuclear systems, are properly taken into account.

Using a combination of one- and two-dimensional methods, H-1- and N-15-nmr spectroscopy has been employed to perform the complete assignment and the structural determination of the immunogenic undecapeptide CTTTNSRGTTT in DMSO solution. Nuclear Overhauser enhancement spectroscopy experiments indicated the presence of secondary structures, mainly turn-like structures, which only represent a family, albeit a dominant one, of an ensemble of conformations available to the peptide. Since reverse turns may play an important role as intermediates in protein folding, the experimental observations described here may link the immunological and theoretical approaches to protein folding.

The use of soluble spin labels to filter out the cross peaks of outer proton nuclei in 2D NMR spectra has been proposed as a general method to obtain structural information for complex molecules. Here the paramagnetic effects observed on backbone protons of an unfolded 27 amino acid peptide are discussed. The lack of any differential intensity change of the NH–Hα cross-peaks in TOCSY spectra is suggested as an additional general criterion for the identification of unfolded structures.