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

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

Direct Correlation of Cell Toxicity to Conformational Ensembles of Genetic A<i>β </i>Variants

We report a systematic analysis of conformational ensembles generated from multiseed molecular dynamics simulations of all 15 known genetic variants of Aβ₄₂. We show that experimentally determined variant toxicities are largely explained by random coil content of the amyloid ensembles (correlation with smaller EC₅₀ values; <i>R</i>² = 0.54, <i>p</i> = 0.01), and to some extent the helix character (more helix-character is less toxic, <i>R</i>² = 0.32, <i>p</i> = 0.07) and hydrophobic surface (<i>R</i>² = 0.37, <i>p</i> = 0.04). Our findings suggest that qualitative structural features of the amyloids, rather than the quantitative levels, are fundamentally related to neurodegeneration. The data provide molecular explanations for the high toxicity of E22 variants and for the protective features of the recently characterized A2T variant. The identified conformational features, for example, the local helix–coil-strand transitions of the C-terminals of the peptides, are of likely interest in the direct targeting of amyloids by rational drug design