Ca2+‐complex stability of GAPAGPLIVPY peptide in gas and aqueous phase,investigated by affinity capillary electrophoresis and molecular dynamics simulations and compared to mass spectrometric results

Strong, sequence‐specific gas‐phase bindings between proline‐rich peptides and alkaline earth metal ions in nanoESI‐MS experiments were reported by Lehmann et al. (Rapid Commun. Mass Spectrom. 2006, 20, 2404–2410), however its relevance for physiological‐like aqueous phase is uncertain. Therefore, the complexes should also be studied in aqueous solution and the relevance of the MS method for binding studies be evaluated. A mobility shift ACE method was used for determining the binding between the small peptide GAPAGPLIVPY and various metal ions in aqueous solution. The findings were compared to the MS results and further explained using computational methods. While the MS data showed a strong alkaline earth ion binding, the ACE results showed nonsignificant binding. The proposed vacuum state complex also decomposed during a molecular dynamic simulation in aqueous solution. This study shows that the formed stable peptide–metal ion adducts in the gas phase by ESI‐MS does not imply the existence of analogous adducts in the aqueous phase. Comparing peptide–metal ion interaction under the gaseous MS and aqueous ACE conditions showed huge difference in binding behavior.     

Biosynthesis of fomannosin. 2H NMR evidence against postulated hydride shifts

²H NMR analysis of fomannosin (1) derived from [5,5-²H₂]-mevalonate established the presence of deuterium at C-5 and C-10, whereas no isotope was located at C-12.     

Comparison of knowledge-based and distance geometry approaches for generation of molecular conformations.

A knowledge-based approach for generating conformations of molecules has been developed. The method described here provides a good sampling of the molecule's conformational space by restricting the generated conformations to those consistent with the reference database. The present approach, internally named et for enumerate torsions, differs from previous database-mining approaches by employing a library of much larger substructures while treating open chains, rings, and combinations of chains and rings in the same manner. In addition to knowledge in the form of observed torsion angles, some knowledge from the medicinal chemist is captured in the form of which substructures are identified. The knowledge-based approach is compared to Blaney et al.'s distance geometry (DG) algorithm for sampling the conformational space of molecules. The structures of 113 protein-bound molecules, determined by X-ray crystallography, were used to compare the methods. The present knowledge-based approach (i) generates conformations closer to the experimentally determined conformation, (ii) generates them sooner, and (iii) is significantly faster than the DG method.     

Asymmetric snap-buckling of a column restrained by a stiff wire

Summary A relatively simple example of asymmetric snap-through buckling in a continuous structure is the nonlinear problem of a cantilevered column restrained at its tip by a stiff wire, which is inclined at an acute angle to the column centerline, and loaded at its tip by a force perpendicular to the centerline. A parameter called , which is the nondimensional ratio of the flexural rigidity of the column to the combined extensional stiffness of the wire and the column centerline, determines the essential features of the buckling. If is zero, or is small compared to unity, the bending of the column is small enough to justify the use of linear bending theory for the column. Hence, even though the constraint is nonlinear, the solution to this problem is obtained in closed form. The critical point for the structure is found to be an asymmetric branching point for =0, while for positive, the critical point is a snap-through type. The effect of is similar to that induced by initial imperfections in more complex structures. For very small , the critical load is markedly decreased from the value for =0. Moreover, the graph of the load vs. tip deflection has the appearance of having an acute discontinuity in slope at the critical point for very small, although it is actually found that the graph has a horizontal tangent there.

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Sommario Un esempio relativamente semplice di collasso asimmetrico per carico di punta in una struttura continua è il problema non lineare di una colonna incastrata ad una estremità e vincolata all'altra estremità da un filo rigido che forma un angolo acuto con l'asse della colonna e caricata a quella estremità con una forza perpendicolare allo stesso asse. Un parametro chiamato , che è il rapporto adimensionale fra la rigidità flessionale della colonna e la rigidezza longitudinale del filo e dell'asse della colonna, determina le caratteristiche essenziali del cedimento. Se è zero o è piccolo rispetto all'unità, l'inflessione della colonna è sufficientemente piccola per giustificare l'uso della teoria lineare di inflessione per la colonna. Di conseguenza anche se il vincolo non è lineare la soluzione del problema è ottenuta in forma compatta. Il punto critico della struttura si trova nel punto di biforcazione asimmetrica per =0, mentre per positivo, il punto critico rappresenta un punto di collasso. L'effetto di è simile a quello prodotto da imperfezioni iniziali in strutture più complesse. Per molto piccolo il carico critico è notevolmente ridotto rispetto al valore per =0. Inoltre il grafico del carico in funzione della curvatura all'estremità sembra avere una netta discontinuità nella pendenza dal punto di biforcazione per molto piccolo benchè, in realtà si trovi che il grafico ha lì una tangente orizzontale.

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This research was supported by the Advanced Research Projects Agency (Project DEFENDER) and was monitored by the U.S. Army Research Office, Durham, under Contract DA-31-124-ARO-D-257.     

Correction to Extending the trend vector: The trend matrix and sample-based partial least squares

Note

Correction to Extending the trend vector: The trend matrix and sample-based partial least squares     

Sample-distance partial least squares: PLS optimized for many variables,with application to CoMFA

Summary Three-dimensional molecular modeling can provide an unlimited number m of structural properties. Comparative Molecular Field Analysis (CoMFA), for example, may calculate thousands of field values for each model structure. When m is large, partial least squares (PLS) is the statistical method of choice for fitting and predicting biological responses. Yet PLS is usually implemented in a property-based fashion which is optimal only for small m. We describe here a sample-based formulation of PLS which can be used to fit any single response (bioactivity). SAMPLS reduces all explanatory data to the pairwise distances among n sample (molecules), or equivalently to an n-by-n covariance matrix C. This matrix, unmodified, can be used to fit all PLS components. Furthermore, SAMPLS will validate the model by modern resampling techniques, at a cost independent of m. We have implemented SAMPLS as a Fortran program and have reproduced conventional and cross-validated PLS analyses of data from two published studies. Full (leaveach-out) cross-validation of a typical CoMFA takes 0.2 CPU s. SAMPLS is thus ideally suited to structure-activity analysis based on CoMFA fields or bonded topology. The sample-distance formulation also relates PLS to methods like cluster analysis and nonlinear mapping, and shows how drastically PLS simplifies the information in CoMFA fields.Abbreviations PLS partial least squares - SAMPLS sample-distance partial least squares - CoMFA comparative molecular field analysis.