15 research outputs found
Impact of Vibrational Entropy on the Stability of Unsolvated Peptide Helices with Increasing Length
Helices are a key folding motif in
protein structure. The question
of which factors determine helix stability for a given polypeptide
or protein is an ongoing challenge. Here we use van-der-Waals-corrected
density functional theory to address a part of this question in a
bottom-up approach. We show how intrinsic helical structure is stabilized
with length and temperature for a series of experimentally well-studied
unsolvated alanine-based polypeptides, Ac-Ala<sub><i>n</i></sub>-LysH<sup>+</sup>. By exhaustively exploring the conformational
space of these molecules, we find that helices emerge as the preferred
structure in the length range <i>n</i> = 4â8 not
just due to enthalpic factors (hydrogen bonds and their cooperativity,
van der Waals dispersion interactions, electrostatics) but importantly
also by a vibrational entropic stabilization over competing conformers
at room temperature. The stabilization is shown to be due to softer
low-frequency vibrational modes in helical conformers than in more
compact ones. This observation is corroborated by including anharmonic
effects explicitly through <i>ab initio</i> molecular dynamics
and generalized by testing different terminations and considering
larger helical peptide models
Oxidative Dehydrogenation of Methane by Isolated Vanadium Oxide Clusters Supported on Au (111) and Ag (111) Surfaces
We
use density functional theory, with the GGA-PBE functional,
to investigate the ability of vanadium oxide clusters, supported on
Ag or Au, to break the CâH bond in methane. We perform a thermodynamic
analysis to show that the VO<sub>4</sub> cluster is the most likely
oxidant and then proceed to calculate the energy of the dissociative
adsorption of methane and its activation energy. We explain some peculiar
features of the reaction path and propose that they are general for
alkane activation on oxides
Oxidative Dehydrogenation of Methane by Isolated Vanadium Oxide Clusters Supported on Au (111) and Ag (111) Surfaces
We
use density functional theory, with the GGA-PBE functional,
to investigate the ability of vanadium oxide clusters, supported on
Ag or Au, to break the CâH bond in methane. We perform a thermodynamic
analysis to show that the VO<sub>4</sub> cluster is the most likely
oxidant and then proceed to calculate the energy of the dissociative
adsorption of methane and its activation energy. We explain some peculiar
features of the reaction path and propose that they are general for
alkane activation on oxides
Validation Challenge of Density-Functional Theory for Peptidesî¸Example of Ac-Phe-Ala<sub>5</sub>âLysH<sup>+</sup>
We assess the performance of a group
of exchange-correlation functionals
for predicting the secondary structure of peptide chains, up to a
new many-body dispersion corrected hybrid density functional, dubbed
PBE0+MBD* by its original authors. For the purpose of validation,
we first compare to published, high-level benchmark conformational
energy hierarchies (coupled cluster at the singles, doubles, and perturbative
triples level, CCSDÂ(T)) for 73 conformers of small three-residue peptides,
establishing that the van der Waals corrected PBE0 functional yields
an average error of only âź20 meV (âź0.5 kcal/mol). This
compares to âź40â50 meV for nondispersion corrected PBE0
and 40â100 meV for different empirical force fields (estimated
for the alanine tetrapeptide). For longer peptide chains that form
a secondary structure, CCSDÂ(T) level benchmark data are currently
unaffordable. We thus turn to the <i>experimentally</i> well
studied Ac-Phe-Ala<sub>5</sub>-LysH<sup>+</sup> peptide, for which
four closely competing conformers were established by infrared spectroscopy.
For comparison, an exhaustive theoretical conformational space exploration
yields at least 11 competing low energy minima. We show that (i) the
many-body dispersion correction, (ii) the hybrid functional nature
of PBE0+MBD*, and (iii) zero-point corrections are needed to reveal
the four experimentally observed structures as the minima that would
be populated at low temperature
Integer <i>versus</i> Fractional Charge Transfer at Metal(/Insulator)/Organic Interfaces: Cu(/NaCl)/TCNE
Semilocal and hybrid density functional theory was used to study the charge transfer and the energy-level alignment at a representative interface between an extended metal substrate and an organic adsorbate layer. Upon suppressing electronic coupling between the adsorbate and the substrate by inserting thin, insulating layers of NaCl, the hybrid functional localizes charge. The laterally inhomogeneous charge distribution resulting from this spontaneous breaking of translational symmetry is reflected in observables such as the molecular geometry, the valence and core density of states, and the evolution of the work function with molecular coverage, which we discuss for different growth modes. We found that the amount of charge transfer is determined, to a significant extent, by the ratio of the lateral spacing of the molecules and their distance to the metal. Therefore, charge transfer does not only depend on the electronic structure of the individual components but, just as importantly, on the interface geometry
Secondary Structure of Ac-Ala<sub><i>n</i></sub>-LysH<sup>+</sup> Polyalanine Peptides (<i>n</i> = 5,10,15) in Vacuo: Helical or Not?
The polyalanine-based peptide series Ac-Ala<sub><i>n</i></sub>-LysH<sup>+</sup> (<i>n</i> = 5â20) is a prime example that a secondary structure motif that is well-known from the solution phase (here: helices) can be formed in vacuo. Here we revisit the series members <i>n</i> = 5,10,15, using density functional theory (van der Waals corrected generalized gradient approximation) for structure predictions, which are then corroborated by room temperature gas-phase infrared vibrational spectroscopy. We employ a <i>quantitative</i> comparison based on Pendryâs reliability factor (popular in surface crystallography). In particular, including <i>anharmonic</i> effects into calculated spectra by way of ab initio molecular dynamics produces remarkably good experimentâtheory agreement. We find the longer molecules (<i>n</i> = 10,15) to be firmly Îą-helical in character. For <i>n</i> = 5, calculated free-energy differences show different H-bond networks to still compete closely. Vibrational spectroscopy indicates a predominance of Îą-helical motifs at 300 K, but the lowest-energy conformer is not a simple helix
Assessment and Validation of Machine Learning Methods for Predicting Molecular Atomization Energies
The
accurate and reliable prediction of properties of molecules
typically requires computationally intensive quantum-chemical calculations.
Recently, machine learning techniques applied to <i>ab initio</i> calculations have been proposed as an efficient approach for describing
the energies of molecules in their given ground-state structure throughout
chemical compound space (Rupp et al. <i>Phys. Rev. Lett.</i> <b>2012</b>, <i>108</i>, 058301). In this paper
we outline a number of established machine learning techniques and
investigate the influence of the molecular representation on the methods
performance. The best methods achieve prediction errors of 3 kcal/mol
for the atomization energies of a wide variety of molecules. Rationales
for this performance improvement are given together with pitfalls
and challenges when applying machine learning approaches to the prediction
of quantum-mechanical observables
Toward Low-Temperature Dehydrogenation Catalysis: Isophorone Adsorbed on Pd(111)
Adsorbate geometry and reaction dynamics play essential
roles in
catalytic processes at surfaces. Here we present a theoretical and
experimental study for a model functional organic/metal interface:
isophorone (C<sub>9</sub>H<sub>14</sub>O) adsorbed on the Pd(111)
surface. Density functional theory calculations with the PerdewâBurkeâErnzerhoff
(PBE) functional including van der Waals (vdW) interactions, in combination
with infrared spectroscopy and temperature-programmed desorption (TPD)
experiments, reveal the reaction pathway between the weakly chemisorbed
reactant (C<sub>9</sub>H<sub>14</sub>O) and the strongly chemisorbed
product (C<sub>9</sub>H<sub>10</sub>O), which occurs by the cleavage
of four CâH bonds below 250 K. Analysis of the TPD spectrum
is consistent with the relatively small magnitude of the activation
barrier derived from PBE+vdW calculations, demonstrating the feasibility
of low-temperature dehydrogenation
Prognostic Impact of [18F]Fluorothymidine and [18F]Fluoro-D-Glucose Baseline Uptakes in Patients with Lung Cancer Treated First-Line with Erlotinib
<div><p>3â˛-deoxy-3â˛-[<sup>18</sup>F]fluoro-L-thymidine (FLT) and 2â˛-deoxy-2â˛-[<sup>18</sup>F]fluoro-D-glucose (FDG) are used to visualize proliferative and metabolic activity of tumors. In this study we aimed at evaluating the prognostic value of FLT and FDG uptake measured by positron emission tomography (PET) in patients with metastatic non-small cell lung cancer (NSCLC) prior to systemic therapy with erlotinib. FLT and FDG maximum standardized uptake (SUVmax) values per patient were analyzed in 40 chemotherapy naive patients with advanced NSCLC (stage IV) before treatment with erlotinib. Prior therapy median SUVmax was 6.6 for FDG and 3.0 for FLT, respectively. In univariate analysis, patients with an FDG SUVmax <6.6 had a significantly better overall survival (16.3 months [95% confidence interval [CI] 7.1â25.4 months]) compared to patients with an FDG SUVmax âĽ6.6 (3.1 months [95% CI 0.6â5.5 months]) (p<0.001, log rank). Similarly, low FLT uptake (SUVmax <3.0) was associated with significantly longer survival (10.3 months (0â23.3 months, 95% CI) compared to high FLT uptake (3.4 months (0â8.1 months, 95% CI) (pâ=â0.027). The independent prognostic value of baseline FDG uptake was demonstrated in multivariate analysis (pâ=â0.05, Cox regression). These data suggest that baseline SUVmax values for both FDG and FLT PET might be further developed as markers for prognostic stratification of patients in advanced NSCLC treated with tyrosine kinase inhibitors (TKI) directed against the epidermal growth factor receptor (EGFR).</p> <h3>Trial Registration</h3><p>Clinicaltrials.gov, Identifier: <a href="http://clinicaltrials.gov/ct2/show/NCT00568841">NCT00568841</a></p> </div
Individual patient characteristics and PET results.
<p>Individual patient characteristics and PET results.</p