649 research outputs found
Heme isomers substantially affect heme's electronic structure and function
Different vinyl orientations of heme are common in proteins and may affect heme potentials by up to 0.2 V.</p
Genotype-Property Patient-Phenotype Relations Suggest that Proteome Exhaustion Can Cause Amyotrophic Lateral Sclerosis
Late-onset neurodegenerative diseases remain poorly understood as search continues for the perceived pathogenic protein species. Previously, variants in Superoxide Dismutase 1 (SOD1) causing Amyotrophic Lateral Sclerosis (ALS) were found to destabilize and reduce net charge, suggesting a pathogenic aggregation mechanism. This paper reports analysis of compiled patient data and experimental and computed protein properties for variants of human SOD1, a major risk factor of ALS. Both stability and reduced net charge correlate significantly with disease, with larger significance than previously observed. Using two independent methods and two data sets, a probability < 3% (t-statistical test) is found that ALS-causing mutations share average stability with all possible 2907 SOD1 mutations. Most importantly, un-weighted patient survival times correlate strongly with the misfolded/unfolded protein copy number, expressed as an exponential function of the experimental stabilities (R2 = 0.31, p = 0.002), and this phenotype is further aggravated by charge (R2 = 0.51, p = 1.8 x 10-5). This finding suggests that disease relates to the copy number of misfolded proteins. Exhaustion of motor neurons due to expensive protein turnover of misfolded protein copies is consistent with the data but can further explain e.g. the expression-dependence of SOD1 pathogenicity, the lack of identification of a molecular toxic mode, elevated SOD1 mRNA levels in sporadic ALS, bioenergetic effects and increased resting energy expenditure in ALS patients, genetic risk factors affecting RNA metabolism, and recent findings that a SOD1 mutant becomes toxic when proteasome activity is recovered after washout of a proteasome inhibitor. Proteome exhaustion is also consistent with energy-producing mitochondria accumulating at the neuromuscular junctions where ALS often initiates. If true, this exhaustion mechanism implies a complete change of focus in treatment of ALS towards actively nursing the energy state and protein turnover of the motor neurons
Comment on "Density functional theory is straying from the path toward the exact functional"
Recently (Science, 355, 6320, 2017, 49-52) it was argued that density
functionals stray from the path towards exactness due to errors in densities
(\rho) of 14 atoms and ions computed with several recent functionals. However,
this conclusion rests on very compact \rho\ of highly charged 1s2 and 1s22s2
systems, the divergence is due to one particular group's recently developed
functionals, whereas other recent functionals perform well, and errors in \rho\
were not compared to actual energies E[\rho] of the same distinct, compact
systems, but to general errors for diverse systems. As argued here, a true path
can only be defined for E[\rho] and \rho\ for the same systems: By computing
errors in E[\rho], it is shown that different functionals show remarkably
linear error relationships between \rho\ and E[\rho] on well-defined but
different paths towards exactness, and the ranking in Science, 355, 6320, 2017,
49-52 breaks down. For example, M06-2X, said to perform poorly, performs very
well on the E,\rho\ paths defined here, and local (non-GGA) functionals rapidly
increase errors in E[\rho] due to the failure to describe dynamic correlation
of compact systems without the gradient. Finally, a measure of "exactness" is
given by the product of errors in E[\rho] and \rho; these relationships may be
more relevant focus points than a time line if one wants to estimate exactness
and develop new exact functionals.Comment: 1 figure (Figure 1A, 1B, 1C) and two tables of supplementary dat
Energy vs. density on paths toward more exact density functionals
Recently, the progression toward more exact density functional theory has
been questioned, implying a need for more formal ways to systematically measure
progress, i.e. a path. Here I use the Hohenberg-Kohn theorems and the
definition of normality by Burke et al. to define a path toward exactness and
straying from the path by separating errors in \r{ho} and E[\r{ho}]. A
consistent path toward exactness involves minimizing both errors. Second, a
suitably diverse test set of trial densities \r{ho}' can be used to estimate
the significance of errors in \r{ho} without knowing the exact densities which
are often computationally inaccessible. To illustrate this, the systems
previously studied by Medvedev et al., the first ionization energies of atoms
with Z = 1 to 10, the ionization energy of water, and the bond dissociation
energies of five diatomic molecules were investigated and benchmarked against
CCSD(T)/aug-cc-pV5Z. A test set of four functionals of distinct designs was
used: B3LYP, PBE, M06, and S-VWN. For atomic cations regardless of charge and
compactness up to Z = 10, the energy effects of variations in \r{ho} are < 4
kJ/mol (chemical accuracy) defined here as normal, even though these four
functionals ranked very differently in the previous test. Thus, the off-path
behavior for such cations is energy-wise insignificant and in fact,
indeterminate because of noise from other errors. An interesting oscillating
behavior in the density sensitivity is observed vs. Z, explained by orbital
occupation effects. Finally, it is shown that even large normal problems such
as the Co-C bond energy of cobalamins can use simpler (e.g. PBE) trial
densities to drastically speed up computation by loss of a few kJ/mol in
accuracy.Comment: 5 Figures in main paper; supporting information contains 14 figures
and 32 table
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