Density functional theory describes matter at the quantum level, but all popular approximations suffer from systematic errors that arise from the violation of mathematical properties of the exact ...functional. We overcame this fundamental limitation by training a neural network on molecular data and on fictitious systems with fractional charge and spin. The resulting functional, DM21 (DeepMind 21), correctly describes typical examples of artificial charge delocalization and strong correlation and performs better than traditional functionals on thorough benchmarks for main-group atoms and molecules. DM21 accurately models complex systems such as hydrogen chains, charged DNA base pairs, and diradical transition states. More crucially for the field, because our methodology relies on data and constraints, which are continually improving, it represents a viable pathway toward the exact universal functional.
Protein structure prediction can be used to determine the three-dimensional shape of a protein from its amino acid sequence
. This problem is of fundamental importance as the structure of a protein ...largely determines its function
; however, protein structures can be difficult to determine experimentally. Considerable progress has recently been made by leveraging genetic information. It is possible to infer which amino acid residues are in contact by analysing covariation in homologous sequences, which aids in the prediction of protein structures
. Here we show that we can train a neural network to make accurate predictions of the distances between pairs of residues, which convey more information about the structure than contact predictions. Using this information, we construct a potential of mean force
that can accurately describe the shape of a protein. We find that the resulting potential can be optimized by a simple gradient descent algorithm to generate structures without complex sampling procedures. The resulting system, named AlphaFold, achieves high accuracy, even for sequences with fewer homologous sequences. In the recent Critical Assessment of Protein Structure Prediction
(CASP13)-a blind assessment of the state of the field-AlphaFold created high-accuracy structures (with template modelling (TM) scores
of 0.7 or higher) for 24 out of 43 free modelling domains, whereas the next best method, which used sampling and contact information, achieved such accuracy for only 14 out of 43 domains. AlphaFold represents a considerable advance in protein-structure prediction. We expect this increased accuracy to enable insights into the function and malfunction of proteins, especially in cases for which no structures for homologous proteins have been experimentally determined
.
We describe AlphaFold, the protein structure prediction system that was entered by the group A7D in CASP13. Submissions were made by three free‐modeling (FM) methods which combine the predictions of ...three neural networks. All three systems were guided by predictions of distances between pairs of residues produced by a neural network. Two systems assembled fragments produced by a generative neural network, one using scores from a network trained to regress GDT_TS. The third system shows that simple gradient descent on a properly constructed potential is able to perform on par with more expensive traditional search techniques and without requiring domain segmentation. In the CASP13 FM assessors' ranking by summed z‐scores, this system scored highest with 68.3 vs 48.2 for the next closest group (an average GDT_TS of 61.4). The system produced high‐accuracy structures (with GDT_TS scores of 70 or higher) for 11 out of 43 FM domains. Despite not explicitly using template information, the results in the template category were comparable to the best performing template‐based methods.
The Integrated Science Investigation of the Sun (ISIS) is a complete science investigation on the Solar Probe Plus (SPP) mission, which flies to within nine solar radii of the Sun’s surface. ISIS ...comprises a two-instrument suite to measure energetic particles over a very broad energy range, as well as coordinated management, science operations, data processing, and scientific analysis. Together, ISIS observations allow us to explore the mechanisms of energetic particles dynamics, including their: (1) Origins—defining the seed populations and physical conditions necessary for energetic particle acceleration; (2) Acceleration—determining the roles of shocks, reconnection, waves, and turbulence in accelerating energetic particles; and (3) Transport—revealing how energetic particles propagate from the corona out into the heliosphere. The two ISIS Energetic Particle Instruments measure lower (EPI-Lo) and higher (EPI-Hi) energy particles. EPI-Lo measures ions and ion composition from ∼20 keV/nucleon–15 MeV total energy and electrons from ∼25–1000 keV. EPI-Hi measures ions from ∼1–200 MeV/nucleon and electrons from ∼0.5–6 MeV. EPI-Lo comprises 80 tiny apertures with fields-of-view (FOVs) that sample over nearly a complete hemisphere, while EPI-Hi combines three telescopes that together provide five large-FOV apertures. ISIS observes continuously inside of 0.25 AU with a high data collection rate and burst data (EPI-Lo) coordinated with the rest of the SPP payload; outside of 0.25 AU, ISIS runs in low-rate science mode whenever feasible to capture as complete a record as possible of the solar energetic particle environment and provide calibration and continuity for measurements closer in to the Sun. The ISIS Science Operations Center plans and executes commanding, receives and analyzes all ISIS data, and coordinates science observations and analyses with the rest of the SPP science investigations. Together, ISIS’ unique observations on SPP will enable the discovery, untangling, and understanding of the important physical processes that govern energetic particles in the innermost regions of our heliosphere, for the first time. This paper summarizes the ISIS investigation at the time of the SPP mission Preliminary Design Review in January 2014.
Gerasimov
et al
. claim that the ability of DM21 to respect fractional charge (FC) and fractional spin (FS) conditions outside of the training set has not been demonstrated in our paper. This is ...based on (i) asserting that the training set has a ~50% overlap with our bond-breaking benchmark (BBB) and (ii) questioning the validity and accuracy of our other generalization examples. We disagree with their analysis and believe that the points raised are either incorrect or not relevant to the main conclusions of the paper and to the assessment of general quality of DM21.
A small molecule called PD 153035 inhibited the epidermal growth factor (EGF) receptor tyrosine kinase with a 5-pM inhibition constant. The inhibitor was specific for the EGF receptor tyrosine kinase ...and inhibited other purified tyrosine kinases only at micromolar or higher concentrations. PD 153035 rapidly suppressed autophosphorylation of the EGF receptor at low nanomolar concentrations in fibroblasts or in human epidermoid carcinoma cells and selectively blocked EGF-mediated cellular processes including mitogenesis, early gene expression, and oncogenic transformation. PD 153035 demonstrates an increase in potency over that of other tyrosine kinase inhibitors of four to five orders of magnitude for inhibition of isolated EGF receptor tyrosine kinase and three to four orders of magnitude for inhibition of cellular phosphorylation.
A class of high-affinity inhibitors is disclosed that selectively target and irreversibly inactivate the epidermal growth factor receptor tyrosine kinase through specific, covalent modification of a ...cysteine residue present in the ATP binding pocket. A series of experiments employing MS, molecular modeling, site-directed mutagenesis, and 14C-labeling studies in viable cells unequivocally demonstrate that these compounds selectively bind to the catalytic domain of the epidermal growth factor receptor with a 1:1 stoichiometry and alkylate Cys-773. While the compounds are essentially non-reactive in solution, they are subject to rapid nucleophilic attack by this particular amino acid when bound in the ATP pocket. The molecular orientation and positioning of the acrylamide group in these inhibitors in relation to Cys-773 entirely support these results as determined from docking experiments in a homology-built molecular model of the ATP site. Evidence is also presented to indicate that the compounds interact in an analogous fashion with erbB2 but have no activity against the other receptor tyrosine kinases or intracellular tyrosine kinases that were tested in this study. Finally, a direct comparison between 6-acrylamido-4-anilinoquinazoline and an equally potent but reversible analog shows that the irreversible inhibitor has far superior in vivo antitumor activity in a human epidermoid carcinoma xenograft model with no overt toxicity at therapeutically active doses. The activity profile for this compound is prototypical of a generation of tyrosine kinase inhibitors with great promise for therapeutic significance in the treatment of proliferative disease.
A series of 6- and 7-acrylamide derivatives of the 4-(phenylamino)quinazoline and -pyridopyrimidine classes of epidermal growth factor receptor (EGFR) inhibitors were prepared from the corresponding ...amino compounds by reaction with either acryloyl chloride/base or acrylic acid/1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride. All of the 6-acrylamides, but only the parent quinazoline 7-acrylamide, were irreversible inhibitors of the isolated enzyme, confirming that the former are better-positioned, when bound to the enzyme, to react with the critical cysteine-773. Quinazoline, pyrido3,4-dpyrimidine, and pyrido3,2-dpyrimidine 6-acrylamides were all irreversible inhibitors and showed similar high potencies in the enzyme assay (likely due to titration of the available enzyme). However the pyrido3,2-dpyrimidine analogues were 2−6-fold less potent than the others in a cellular autophosphorylation assay for EGFR in A431 cells. The quinazolines were generally less potent overall toward inhibition of heregulin-stimulated autophosphorylation of erbB2 (in MDA-MB-453-cells), whereas the pyridopyrimidines were equipotent. Selected compounds were evaluated in A431 epidermoid and H125 non-small-cell lung cancer human tumor xenografts. The compounds showed better activity when given orally than intraperitoneally. All showed significant tumor growth inhibition (stasis) over a dose range. The poor aqueous solubility of the compounds was a drawback, requiring formulation as fine particulate emulsions.
The migration of 1,263 adult radio‐tagged steelhead Oncorhynchus mykiss was assessed in the Nass, Skeena, Bella Coola, Fraser, and mid‐Columbia rivers from 1993 to 2001. Of the summer‐run steelhead ...tagged in the mid‐Columbia River, 80–87% eventually continued their upstream migration after being tagged, and 87–90% of those were detected in spawning areas. Similar results were seen for summer‐run steelhead tracked on the Nass and Skeena rivers. Mid‐Columbia summer‐run steelhead stocks that passed five dams en route to their spawning destinations (Methow and Okanogan rivers) traveled at a median rate of 20 km/d, which exceeded the median rates for summer‐run steelhead tracked on the Nass (3.8 km/d) and Skeena rivers (12–16 km/d). The upstream migration rates were best explained by river gradient and distance of the study area from the ocean. When the effects of river gradient and reach location were taken into account, impoundment was still a significant factor increasing the upstream migration speeds of summer‐run steelhead. Kelting speeds varied widely among rivers and did not appear to be a function of gradient.
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