Strategies for protein folding and design

Fundamental challenges in molecular biology can be addressed by using simple models on a lattice, where statistical mechanics and combinatoric techniques can be employed. The basic premise is that it is sensible to test any proposed method on the simplest of models in order to assess their validity before launching a full-scale attack on realistic problems. In this paper we follow this strategy and we present different efficient schemes to perform protein design and to extract effective amino acid interaction potentials.This work was supported in part by INFM, INFN sez. di Trieste, NASA and NATO.     

Equation of Motion of an Electric Charge

The appearance of the time derivative of the acceleration in the equation of motion (EOM) of an electric charge is studied. It is shown that when an electric charge is accelerated, a stress force exists in the curved electric field of the accelerated charge, and in the case of a constant linear acceleration, this force is proportional to the acceleration. This stress force acts as a reaction force which is responsible for the creation of the radiation (instead of the radiation reaction force that actually does not exist at low velocities). Thus the initial acceleration should be supplied as an initial condition for the solution of the EOM of an electric charge.     

Design, synthesis, and evaluation of azepine-based cryptophycin mimetics

Cryptophycins, depsipeptides isolated from terrestrial blue-green algae, show potent activity against a variety of tumor cell lines. Given the potential of the cryptophycins for cancer therapy, we developed a new class of non-peptide peptidomimetic, designed to replace the 16-membered macrolide ring with a 7-membered azepine ring for attachment of the cryptophycin side chains with the required spatial orientation to mimic the conformation of the relevant region of the natural product. Monte Carlo conformational analysis revealed excellent overlay of the local minimum structural model 6 and X-ray structure of (+)-cryptophycin-3 (5). Starting from this structural model, we designed and synthesized compounds (+)-25, (+)-30, and (+)-34 as potential mimics of cryptophycins. Compounds (+)-25, (+)-30, and (+)-34 were tested for in vitro cytotoxicity against six human cancer cell lines. Although only modest activities were observed, these results suggested that a new series of bioactive cryptophycin analogues might be available by structural modification of the central ring system of the cryptophycins.     

Phase equilibria, crystal structures, and dielectric anomaly in the BaZrO3-CaZrO3 system

Phase equilibria in the (1−x)BaZrO₃-xCaZrO₃ system were analyzed using a combination of X-ray and neutron powder diffraction, and transmission electron microscopy. The proposed phase diagram features two extended two-phase fields containing mixtures of a Ba-rich cubic phase and a tetragonal, or orthorhombic Ca-rich phase, all having perovskite-related structures. The symmetry differences in the Ca-rich phases are caused by different tilting patterns of the [ZrO₆] octahedra. In specimens quenched from 1650°C, CaZrO₃ dissolves only a few percent of Ba, whereas the solubility of Ca in BaZrO₃ is approximately . The BaZrO₃-CaZrO₃ system features at least two tilting phase transitions, Pm3m→I4/mcm and I4/mcm→Pbnm. Rietveld refinements of the Ba_0.8Ca_0.2ZrO₃ structure using variable-temperature neutron powder diffraction data confirmed that the Pm3m→I4/mcm transition corresponds to a rotation of octahedra about one of the cubic axes; successive octahedra along this axis rotate in opposite directions. In situ variable-temperature electron diffraction studies indicated that the transition temperature increases with increasing Ca-substitution on the A-sites, from approximately −120°C at Ca to 225°C at Ca. Dielectric measurements revealed that the permittivity increases monotonically from 36 for BaZrO₃ to 53 for Ba_0.9Ca_0.1ZrO₃, and then decreases to 50 for Ba_0.8Ca_0.2ZrO₃. This later specimen was the Ca-richest composition for which pellets could be quenched from the single-phase cubic field with presently available equipment. Strongly non-monotonic behavior was also observed for the temperature coefficient of resonant frequency; however, in this case, the maximum occurred at a lower Ca concentration, 0.05?x?0.1. The non-linear behavior of the dielectric properties was attributed to two competing structural effects: a positive effect associated with substitution of relatively small Ca cations on the A-sites, resulting in stretched Ca-O bonds, and a negative effect, related to the distortion of the A-site environment (bond strain relaxation) upon octahedral tilting.     

How Taxol stabilises microtubule structure

The structure of tubulin shows paclitaxel (Taxol(R)) binding to a pocket in beta tubulin on the microtubule's inner surface, which counteracts the effects of GTP hydrolysis occurring on the other side of the monomer.     

Avermectin-milbemycin studies. 4. An expedient two-step preparation of p-hydroxybenzoates

Dianions derived from a variety of 1,3-diketones react with $\text{Z}$-ethyl-3-bromopropenoate to afford unsaturated diketoesters which upon treatment with base undergo facile cyclization-dehydration to p-hydroxybenzoates.     

A change of variable for the perturbation parameter in rayleigh–Schrödinger perturbation theory

The Feenberg–Goldhammer change of scale, whereby the H₀ in perturbation theory is replaced by (1/μ)H₀ with μ a scaling parameter, is shown to be equivalent to a change of variable for the perturbation parameter. A more general change of variable is shown to lead to a perturbation series with perturbation energies E₃, …, E_2n+1 equal to zero. The resulting energy through (2n + 1)th order has the same form as that found from the Brillouin–Wigner series by different methods.     

Electron densities from the Brueckner Doubles method

Summary The concept of the Brueckner orbital is examined, following a resurgence of interest in wavefunctions constructed from them. The distinction between Self Consistent Field, Natural and Brueckner orbitals are discussed. Total electron densities are calculated for several examples, and correlation densities are studied. It is found that the Brueckner orbitals are more localised than SCF orbitals. The total electron density constructed from the Brueckner reference determinant with Brueckner orbitals gives qualitatively similar pictures as other correlated methods. Brueckner orbitals are found to show dissociation well.     

Single-nucleotide-specific PNA-peptide ligation on synthetic and PCR DNA templates

DNA-directed chemical synthesis has matured into a useful tool with applications such as fabrication of defined (nano)molecular architectures, evolution of amplifiable small-molecule libraries, and nucleic acid detection. Most commonly, chemical methods were used to join oligonucleotides under the control of a DNA or RNA template. The full potential of chemical ligation reactions can be uncovered when nonnatural oligonucleotide analogues that can provide new opportunities such as increased stability, DNA affinity, hybridization selectivity, and/or ease and accuracy of detection are employed. It is shown that peptide nucleic acid (PNA) conjugates, nonionic biostable DNA analogues, allowed the fashioning of highly chemoselective and sequence-selective peptide ligation methods. In particular, PNA-mediated native chemical ligations proceed with sequence selectivities and ligation rates that reach those of ligase-catalyzed oligodeoxynucleotide reactions. Usually, sequence-specific ligations can only be achieved by employing short-length probes, which show DNA affinities that are too low to allow stable binding to target segments in large, double-stranded DNA. It is demonstrated that the PNA-based ligation chemistry allowed the development of a homogeneous system in which rapid single-base mutation analyses can be performed even on double-stranded PCR DNA templates.