20 research outputs found
A Fast Scan Submillimeter Spectroscopic Technique
A new fast scan submillimeter spectroscopic technique (FASSST) has been developed which uses a voltage tunable backward wave oscillator (BWO) as a primary source of radiation, but which uses fast scan (~105 Doppler limited resolution elements/s) and optical calibration methods rather than the more traditional phase or frequency lock techniques. Among its attributes are (1) absolute frequency calibration to ~1/10 of a Doppler limited gaseous absorption linewidth (\u3c0.1 MHz, 0.000 003 cm-1), (2) high sensitivity, and (3) the ability to measure many thousands of lines/s. Key elements which make this system possible include the excellent short term spectral purity of the broadly (~100 GHz) tunable BWO; a very low noise, rapidly scannable high voltage power supply; fast data acquisition; and software capable of automated calibration and spectral line measurement. In addition to the unique spectroscopic power of the FASSST system, its implementation is simple enough that it has the prospect of impacting a wide range of scientific problems
Prevalence of the thioamide {···H-N-C=S}2 synthon-solid-state (X-ray crystallography), solution (NMR) and gas-phase (theoretical) structures of O-methyl-N-aryl-thiocarbamides
Structural investigations, i.e. solid-state (X-ray), solution (1H NMR) and gas-phase (theoretical), on molecules with the general formula MeOC(S)N(H)C6H4-4-Y: Y = H (1), NO2 (2), C(O)Me (3), Cl (4) have shown a general preference for the adoption of an E-conformation about the central C–N bond. Such a conformation allows for the formation of a dimeric hydrogen-bonded {H–N–C=S}2 synthon as the building block. In the cases of 1–3, additional C–H...O interactions give rise to the formation of tapes of varying topology. A theoretical analysis shows that the preference for the E-conformation is about the same as the crystal packing stabilisation energy and consistent with this, the compound with Y = C(O)OMe, (5), adopts a Z-conformation in the solid-state that facilitates the formation of N–H...O, C–H...O and C–H...S interactions, leading to a layer structure. Global crystal packing considerations are shown to be imperative in dictating the conformational form of molecules 1–5.<br /
HIV-1 Env associates with HLA-C free-chains at the cell membrane modulating viral infectivity
HLA-C has been demonstrated to associate with HIV-1 envelope glycoprotein (Env). Virions lacking HLA-C have reduced infectivity and increased susceptibility to neutralizing antibodies. Like all others MHC-I molecules, HLA-C requires \u3b22-microglobulin (\u3b22m) for appropriate folding and expression on the cell membrane but this association is weaker, thus generating HLA-C free-chains on the cell surface. In this study, we deepen the understanding of HLA-C and Env association by showing that HIV-1 specifically increases the amount of HLA-C free chains, not bound to \u3b22m, on the membrane of infected cells. The association between Env and HLA-C takes place at the cell membrane requiring \u3b22m to occur. We report that the enhanced infectivity conferred to HIV-1 by HLA-C specifically involves HLA-C free chain molecules that have been correctly assembled with \u3b22m. HIV-1 Env-pseudotyped viruses produced in the absence of \u3b22m are less infectious than those produced in the presence of \u3b22m. We hypothesize that the conformation and surface expression of HLA-C molecules could be a discriminant for the association with Env. Binding stability to \u3b22m may confer to HLA-C the ability to preferentially act either as a conventional immune-competent molecule or as an accessory molecule involved in HIV-1 infectivity
A novel Alzheimer disease locus located near the gene encoding tau protein
This is the author accepted manuscript. The final version is available from the publisher via the DOI in this recordAPOE ε4, the most significant genetic risk factor for Alzheimer disease (AD), may mask effects of other loci. We re-analyzed genome-wide association study (GWAS) data from the International Genomics of Alzheimer's Project (IGAP) Consortium in APOE ε4+ (10 352 cases and 9207 controls) and APOE ε4- (7184 cases and 26 968 controls) subgroups as well as in the total sample testing for interaction between a single-nucleotide polymorphism (SNP) and APOE ε4 status. Suggestive associations (P<1 × 10-4) in stage 1 were evaluated in an independent sample (stage 2) containing 4203 subjects (APOE ε4+: 1250 cases and 536 controls; APOE ε4-: 718 cases and 1699 controls). Among APOE ε4- subjects, novel genome-wide significant (GWS) association was observed with 17 SNPs (all between KANSL1 and LRRC37A on chromosome 17 near MAPT) in a meta-analysis of the stage 1 and stage 2 data sets (best SNP, rs2732703, P=5·8 × 10-9). Conditional analysis revealed that rs2732703 accounted for association signals in the entire 100-kilobase region that includes MAPT. Except for previously identified AD loci showing stronger association in APOE ε4+ subjects (CR1 and CLU) or APOE ε4- subjects (MS4A6A/MS4A4A/MS4A6E), no other SNPs were significantly associated with AD in a specific APOE genotype subgroup. In addition, the finding in the stage 1 sample that AD risk is significantly influenced by the interaction of APOE with rs1595014 in TMEM106B (P=1·6 × 10-7) is noteworthy, because TMEM106B variants have previously been associated with risk of frontotemporal dementia. Expression quantitative trait locus analysis revealed that rs113986870, one of the GWS SNPs near rs2732703, is significantly associated with four KANSL1 probes that target transcription of the first translated exon and an untranslated exon in hippocampus (P≤1.3 × 10-8), frontal cortex (P≤1.3 × 10-9) and temporal cortex (P≤1.2 × 10-11). Rs113986870 is also strongly associated with a MAPT probe that targets transcription of alternatively spliced exon 3 in frontal cortex (P=9.2 × 10-6) and temporal cortex (P=2.6 × 10-6). Our APOE-stratified GWAS is the first to show GWS association for AD with SNPs in the chromosome 17q21.31 region. Replication of this finding in independent samples is needed to verify that SNPs in this region have significantly stronger effects on AD risk in persons lacking APOE ε4 compared with persons carrying this allele, and if this is found to hold, further examination of this region and studies aimed at deciphering the mechanism(s) are warranted
Many-Body Basis Set Superposition Effect
The basis set superposition
effect (BSSE) arises in electronic structure calculations of molecular
clusters when questions relating to interactions between monomers
within the larger cluster are asked. The binding energy, or total
energy, of the cluster may be broken down into many smaller subcluster
calculations and the energies of these subsystems linearly combined
to, hopefully, produce the desired quantity of interest. Unfortunately,
BSSE can plague these smaller fragment calculations. In this work,
we carefully examine the major sources of error associated with reproducing
the binding energy and total energy of a molecular cluster. In order
to do so, we decompose these energies in terms of a many-body expansion
(MBE), where a “body” here refers to the monomers that
make up the cluster. In our analysis, we found it necessary to introduce
something we designate here as a many-ghost many-body expansion (MGMBE).
The work presented here produces some surprising results, but perhaps
the most significant of all is that BSSE effects up to the order of
truncation in a MBE of the total energy cancel exactly. In the case
of the binding energy, the only BSSE correction terms remaining arise
from the removal of the one-body monomer total energies. Nevertheless,
our earlier work indicated that BSSE effects continued to remain in
the total energy of the cluster up to very high truncation order in
the MBE. We show in this work that the vast majority of these high-order
many-body effects arise from BSSE associated with the one-body monomer
total energies. Also, we found that, remarkably, the complete basis
set limit values for the three-body and four-body interactions differed
very little from that at the MP2/aug-cc-pVDZ level for the respective
subclusters embedded within a larger cluster
When are Many-Body Effects Significant?
Many-body effects
are required for an accurate description of both
structure and dynamics of large chemical systems. However, there are
numerous such interactions to consider, and it is not obvious which
ones are significant. We provide a general and fast method for establishing
which small set of three- and four-body interactions are important.
This is achieved by estimating the maximum many-body effects, ϵ<sub>max</sub>, that can arise in a given arrangement of bodies. Through
careful analysis of ϵ<sub>max</sub>, we find two overall causes
for significant many-body interactions. First, many-body induction
propagates in nonbranching paths, that is, in a chain-like manner.
Second, linear arrangements of bodies promote the alignment of the
dipoles to reinforce the many-body interaction. Consequently, compact
and extended linear arrangements are favored. The latter result is
not intuitive as these linear arrangements can lead to significant
many-body effects extending over large distances. For the first time,
this study provides a rigorous explanation as to how cooperative effects
provide enhanced stability in helices making them one of the most
common structures in biomolecules. Not only do these helices promote
linear dipole alignment, but their chain-like structure is consistent
with the way many-body induction propagates. Finally, using ϵ<sub>max</sub> to screen for significant many-body interactions, we are
able to reproduce the total three- and four-body interaction energies
using a small number of individual many-body interactions
Comparing Vibrationally Averaged Nuclear Shielding Constants by Quantum Diffusion Monte Carlo and Second-Order Perturbation Theory
Using the method of modified Shepard’s
interpolation to
construct potential energy surfaces of the H<sub>2</sub>O, O<sub>3</sub>, and HCOOH molecules, we compute vibrationally averaged isotropic
nuclear shielding constants ⟨σ⟩ of the three molecules
via quantum diffusion Monte Carlo (QDMC). The QDMC results are compared
to that of second–order perturbation theory (PT), to see if
second-order PT is adequate for obtaining accurate values of nuclear
shielding constants of molecules with large amplitude motions. ⟨σ⟩
computed by the two approaches differ for the hydrogens and carbonyl
oxygen of HCOOH, suggesting that for certain molecules such as HCOOH
where big displacements away from equilibrium happen (internal OH
rotation), ⟨σ⟩ of experimental quality may only
be obtainable with the use of more sophisticated and accurate methods,
such as quantum diffusion Monte Carlo. The approach of modified Shepard’s
interpolation is also extended to construct shielding constants σ
surfaces of the three molecules. By using a σ surface with the
equilibrium geometry as a single data point to compute isotropic nuclear
shielding constants for each descendant in the QDMC ensemble representing
the ground state wave function, we reproduce the results obtained
through ab initio computed σ to within statistical noise. Development
of such an approach could thereby alleviate the need for any future
costly ab initio σ calculations
The Combined Fragmentation and Systematic Molecular Fragmentation Methods
ConspectusChemistry, particularly organic chemistry, is mostly concerned
with functional groups: amines, amides, alcohols, ketones, and so
forth. This is because the reactivity of molecules can be categorized
in terms of the reactions of these functional groups, and by the influence
of other adjacent groups in the molecule. These simple truths ought
to be reflected in the electronic structure and electronic energy
of molecules, as reactivity is determined by electronic structure.
However, sophisticated ab initio quantum calculations of the molecular
electronic energy usually do not make these truths apparent. In recent
years, several computational chemistry groups have discovered methods
for estimating the electronic energy as a sum of the energies of small
molecular fragments, or small sets of groups. By decomposing molecules
into such fragments of adjacent functional groups, researchers can
estimate the electronic energy to chemical accuracy; not just qualitative
trends, but accurate enough to understand reactivity. In addition,
this has the benefit of cutting down on both computational time and
cost, as the necessary calculation time increases rapidly with an
increasing number of electrons. Even with steady advances in computer
technology, progress in the study of large molecules is slow.In this Account, we describe two related “fragmentation”
methods for treating molecules, the combined fragmentation method
(CFM) and systematic molecular fragmentation (SMF). In addition, we
show how we can use the SMF approach to estimate the energy and properties
of nonconducting crystals, by fragmenting the periodic crystal structure
into relatively small pieces. A large part of this Account is devoted
to simple overviews of how the methods work.We also discuss
the application of these approaches to calculating
reactivity and other useful properties, such as the NMR and vibrational
spectra of molecules and crystals. These applications rely on the
ability of these fragmentation methods to accurately estimate derivatives
of the molecular and crystal energies. Finally, to provide some common
applications of CFM and SMF, we present some specific examples of
energy calculations for moderately large molecules. For computational
chemists, this fragmentation approach represents an important practical
advance. It reduces the computer time required to estimate the energies
of molecules so dramatically, that accurate calculations of the energies
and reactivity of very large organic and biological molecules become
feasible
FASSST: A New Gas-Phase Analytical Tool
Fast-scan submillimeter spectroscopy technique offers general analytical utility, speed, and detection capability