R.D. Enriz

In Silico Study of Full-Length Amyloid β 1−42 Tri- and Penta-Oligomers in Solution

Amyloid oligomers are considered to play causal roles in the pathogenesis of amyloid-related degenerative diseases including Alzheimers disease. Using MD simulation techniques, we explored the contributions of the different structural elements of trimeric and pentameric full-length Abeta1-42 aggregates in solution to their stability and conformational dynamics. We found that our models are stable at a temperature of 310 K, and converge toward an interdigitated side-chain packing for intermolecular contacts within the two beta-sheet regions of the aggregates: beta1 (residues 18-26) and beta2 (residues 31-42). MD simulations reveal that the beta-strand twist is a characteristic element of Abeta-aggregates, permitting a compact, interdigitated packing of side chains from neighboring beta-sheets. The beta2 portion formed a tightly organized beta-helix, whereas the beta1 portion did not show such a firm structural organization, although it maintained its beta-sheet conformation. Our simulations indicate that the hydrophobic core comprising the beta2 portion of the aggregate is a crucial stabilizing element in the Abeta aggregation process. On the basis of these structure-stability findings, the beta2 portion emerges as an optimal target for further antiamyloid drug design.

Peptide and protein folding

Abstract Ab initio peptide folding, and its role in the reductionistic approach towards the understanding of protein folding are discussed from the points of view of past, present and possible future developments. It is believed that after the initial holistic approach, we are now at a new epoch, which will be dominated by reductionism. New quantitative mathematical models will be the result of the reductionistic approach that will lead toward a new, more sophisticated holistic era.

An exploratory ab initio study of the full conformational space of N-acetyl-l-cysteine-N-methylamide

Abstract The full conformational space of N -acetyl- l -cysteine- N -methylamide was explored by ab initio MO computations. On the Ramachandran hypersurface of four independent variables E = E ( φ , ψ , χ 1 , χ 2 ), 47 conformers were located instead of the expected 3 4 =81 stable structures. The relative stabilities of the various conformers were analyzed in terms of side-chain–backbone interactions covering both hydrogen bonding and charge-transfer types. The stabilization energies exerted by the side-chain of cysteine on the backbone were compared to those of other amino acids.

Peptide models XXIX. cis-trans Isomerism of peptide bonds: ab initio study on small peptide model compound; the 3D-Ramachandran map of formylglycinamide

Thermodynamic separations for cis and trans-amides and formylglycinamide range from 0.00 to 4.77 kcal/mol as computed at various levels of theory. The barriers for trans! cis-isomerization, for the same set of compounds, computed at various levels of theory, were found between 15.69 and 22.67 kcal/mol. The cis- and trans-Ramachandran maps of formylglycinamide are compared and the topology of the ab initio 3D-Ramachandran map is presented for the first time.q 2000 Elsevier Science B.V. All rights reserved.

Peptide models XXV. Side-chain conformational potential energy surface, E = E(χ1, χ2) of N-formyl-L-aspartic acidamide and its conjugate base N- formyl-L-aspartatamide in their γ(L) backbone conformations

Abstract Ab initio molecular computations were carried out on the γ l backbone conformation of N -formyl- l -aspartic acidamide and its conjugate base N -formyl- l -aspartatamide at the HF/3-21G level of theory. All side-chain conformations were explored for the parent amino acid diamide and its conjugate base. Propionate ion, propionic acid, 3,3-difluoropropionate ion and 3,3-difluoropropionic acid were used to model the side-chain in the anionic and neutral compounds.

Characteristics of Ramachandran maps of L-alanine diamides as computed by various molecular mechanics, semiempirical and ab initio MO methods. A search for primary standard of peptide conformational stability

Abstract The optimized geometries and relative energies obtained by four force field and two semi-empirical methods were compared with ab initio results computed for formyl- L -alaninamide. Not all methods yielded the same number of minimum energy conformers. Furthermore, while the optimized geometries of the conformers found were comparable, the computed relative energies varied substantially. Also, the force field calculations produced Ramachandran maps that did not even have the appearance of the ab initio Ramachandran map. Correlating the ab initio relative energies (Δ E ) or free energy (Δ G ) with the log of relative populations, ln( p x / p γ L ), led to linear relationships from which four conformers deviated; two of them (α L and e L ) were overly destabilized and two of them (γ L and γ D ) were over-stabilized. It is suggested that, after such deviations are corrected, a primary standard may be obtained that might be useful in further investigations related to force-field parametrization as well as protein folding.

Penetratin and derivatives acting as antifungal agents

The synthesis, in vitro evaluation, and conformational study of RQIKIWFQNRRMKWKK-NH(2) (penetratin) and related derivatives acting as antifungal agents are reported. Penetratin and some of its derivatives displayed antifungal activity against the human opportunistic pathogenic standardized ATCC strains Candida albicans and Cryptococcus neoformans as well as clinical isolates of C. neoformans. Among the compounds tested, penetratin along with the nonapeptide RKWRRKWKK-NH(2) and the tetrapeptide RQKK-NH(2) exhibited significant antifungal activities against the Cryptococcus species. A comprehensive conformational analysis on the peptides reported here using three different approaches, molecular mechanics, simulated annealing and molecular dynamics simulations, was carried out. The experimental and theoretical results allow us to identify a topographical template which may provide a guide for the design of new compounds with antifungal characteristics against C. neoformans.

A GEOMETRICAL ALGORITHM TO SEARCH THE CONFORMATIONAL SPACE (GASCOS) OF FLEXIBLE MOLECULES

We report a geometrical algorithm to search the conformational space (GASCOS), with the goal to evaluate, in a computationally effective way, all possible conformations of a flexible molecule. The present report itself consists of two parts. The first part is primarily devoted to the mathematical principles on which our approach is based. The basic principles are illustrated in terms of the conformational aspect of small normal hydrocarbons: CnH2n12. In the second half of the paper we apply the geometrical approach to a set of specific chemical problems namely, partially fluorinated propanes are used in order to determine the steric requirement and, therefore, the spatial proximity of the terminal atoms during multiple internal rotations. In one type of application the torsion about the bond was regarded as a continuous variable by choosing the increment in torsional angle (Du )t o be small, such as 58. In this approach we were able to assess the spatial requirement and therefore any possible collision of rotating moieties. In an other type of application Du was assumed to be as large as 1208, thus the internal rotational angle was regarded as a variable that can assume only discrete values (g 1 , a, g 2 ). In this fashion, the program could generate an input file for empirical force field, semi-empirical MO or ab initio molecular computations within the framework of multidimensional conformational analysis (MDCA). In other words GASCOS could become the driver program for any energy calculating software. Finally, when an unusually short distance was obtained by the GASCOS method, it was then possible to consider such an occurrence as an indicator of a probable conformational catastrophe. q 1999 Elsevier Science B.V. All rights reserved.

A search for C–H⋯O type hydrogen bonds in Lamivudine (3TC). An exploratory conformational and electronic analysis

Abstract A conformational study of the molecule Lamivudine (3TC), or cis-1-[2′-hydroxymethyl-5′-(1,3-oxathiolanyl)] cytosine, was carried out. Rotation about the C–N bond (ϕ1) and about the C–CH2(OH) bond (ϕ2), which connects the hydroxymethyl group to the five member ring, led to a conformational potential energy surface. The conformational potential energy 2D map, obtained at the HF/3-21G level of theory, had several minima. A topological analysis of the electron density was carried out on four selected ab initio minimum energy conformations, using judiciously constructed hartree–fock (RHF) wave functions. In order to see all possible hydrogen bonding, the DFT wave function was generated using a mixed basis set; a 6-311++G∗∗ basis was employed on atoms involved in hydrogen bonding interactions and a 3-21G basis on all other atoms. For this analysis the theory of atoms in molecules, developed by Bader, was used. The stability of the intramolecular hydrogen bonding interactions was analyzed in terms of the results obtained.

An ab initio exploratory study of side chain conformations for selected backbone conformations of N-acetyl-l-glutamine-N-methylamide

Abstract The backbone potential energy surface (PES) (Ramachandran map) of N-acetyl- l -glutamine-N-methylamide has been studied at a,a side-chain orientation. Side-chain PESs at selected backbone conformations (γ l and β l ) were also studied. Side-chain–backbone interactions were analyzed in terms of energy and geometry.