Autonomous intelligent agents for accelerated materials discovery

We present an end-to-end computational system for autonomous materials discovery. The system aims for cost-effective optimization in large, high-dimensional search spaces of materials by adopting a sequential, agent-based approach to deciding which experiments to carry out. In choosing next experiments, agents can make use of past knowledge, surrogate models, logic, thermodynamic or other physical constructs, heuristic rules, and different exploration–exploitation strategies. We show a series of examples for (i) how the discovery campaigns for finding materials satisfying a relative stability objective can be simulated to design new agents, and (ii) how those agents can be deployed in real discovery campaigns to control experiments run externally, such as the cloud-based density functional theory simulations in this work. In a sample set of 16 campaigns covering a range of binary and ternary chemistries including metal oxides, phosphides, sulfides and alloys, this autonomous platform found 383 new stable or nearly stable materials with no intervention by the researchers.

We present an end-to-end computational system for autonomous materials discovery.     

Utility of 4,6-dichloro-2-(methylthio)-5-nitropyrimidine. Part 2: Solution phase synthesis of tetrasubstituted purines

A simple synthesis of tetrasubstituted purines is disclosed based on the solution phase elaboration of 4,6-dichloro-2-methylthio-5-nitropyrimidine. One-pot sequential C4 and C6 chloride substitution by secondary and primary amines yields 4,6-diamino-2-methylthio-5-nitropyrimidines. mCPBA-mediated oxidation of the methylthio moiety to the corresponding sulfone allows facile substitution at the 2-position. CrCl₂ assisted reduction of the nitro group, followed by acid catalyzed orthoester cyclization, then provides novel tetrasubstituted purines not accessible by other methods.     

Decoupling the effects of hydrophilic and hydrophobic moieties at the neuron–nanofibre interface

Peptide-based nanofibres are a versatile class of tunable materials with applications in optoelectronics, sensing and tissue engineering. However, the understanding of the nanofibre surface at the molecular level is limited. Here, a series of homologous dilysine–diphenylalnine tetrapeptides were synthesised and shown to self-assemble into water-soluble nanofibres. Despite the peptide nanofibres displaying similar morphologies, as evaluated through atomic force microscopy and neutron scattering, significant differences were observed in their ability to support sensitive primary neurons. Contact angle and labelling experiments revealed that differential presentation of lysine moieties at the fibre surface did not affect neuronal viability; however the mobility of phenylalanine residues at the nanofibre surface, elucidated through solid- and gel-state NMR studies and confirmed through tethered bilayer lipid membrane experiments, was found to be the determining factor in governing the suitability of a given peptide as a scaffold for primary neurons. This work offers new insights into characterising and controlling the nanofibre surface at the molecular level.

The mobility of hydrophobic moieties at a peptide nanofibre surface determines its suitability as a scaffold for sensitive primary cells.     

Competitive Substitution and Electron Transfer in Reactions between Haloamminegold(III) and Halocyanoaurate(III) Complexes and Thiocyanate

Kinetics for reactions between thiocyanate and trans-Au(CN)(2)Cl(2)(-), trans-Au(CN)(2)Br(2)(-), and trans-Au(NH(3))(2)Cl(2)(+) in an acidic, 1.00 M perchlorate aqueous medium have been studied by use of conventional and diode-array UV/vis spectroscopy and high-pressure and sequential-mixing stopped-flow spectrophotometry. Initial, rapid formation of mixed halide-thiocyanate complexes of gold(III) is followed by slower reduction to Au(CN)(2)(-) and Au(NH(3))(2)(+), respectively. This is an intermolecular process, involving attack on the complex by outer-sphere thiocyanate. Second-order rate constants at 25.0 degrees C for reduction of trans-Au(CN)(2)XSCN(-) are (6.9 +/- 1.1) x 10(4) M(-)(1) s(-)(1) for X = Cl and (3.1 +/- 0.7) x 10(3) M(-)(1) s(-)(1) for X = Br. For reduction of trans-Au(CN)(2)(SCN)(2)(-) the second-order rate constant at 25.0 degrees C is (3.1 +/- 0.1) x 10(2) M(-)(1) s(-)(1) and the activation parameters are DeltaH() = (55 +/- 3) x 10(2) kJ mol(-)(1), DeltaS() = (-17.8 +/- 0.8) J K(-)(1) mol(-)(1), and DeltaV() = (-4.6 +/- 0.5) cm(3) mol(-)(1). The activation volume for substitution of one chloride on trans-Au(NH(3))(2)Cl(2)(+) is (-4.5 +/- 0.5) cm(3) mol(-)(1), and that for reduction of trans-Au(NH(3))(2)(SCN)(2)(+) (4.6 +/- 0.9) cm(3) mol(-)(1). The presence of pi-back-bonding cyanide ligands stabilizes the transition states for both substitution and reductive elimination reactions compared to ammine. In particular, complexes trans-Au(CN)(2)XSCN(-) with an unsymmetric electron distribution along the X-Au-SCN axis are reduced rapidly. The observed entropies and volumes of activation reflect large differences in the transition states for the reductive elimination and substitution processes, respectively, the former being more loosely bound, more sensitive to solvational changes, and probably not involving any large changes in the inner coordination sphere. A transition state with an S-S interaction between attacking and coordinated thiocyanate is suggested for the reduction. The stability constants for formation of the very short-lived complex trans-Au(CN)(2)(SCN)(2)(-) from trans-Au(CN)(2)X(SCN)(-) (X = Cl, Br) by replacement of halide by thiocyanate prior to reduction can be calculated from the redox kinetics data to be K(Cl,2) = (3.8 +/- 0.8) x 10(4) and K(Br,2) = (1.1 +/- 0.4) x 10(2).     

Capillary electrophoresis-based analysis of phospholipid and glycosaminoglycan binding by human beta2-glycoprotein I

Human beta2-glycoprotein I (beta2gpI) is a phospholipid and heparin binding plasma glycoprotein involved in autoimmune diseases characterized by blood clotting disturbances (thrombosis) together with the occurrence of autoantibodies against beta2gpI. With the final goal of assessing autoantibody influence on binding interactions of beta2gpI we have studied the development of capillary electrophoresis (CE)-based assays for interactions of negatively charged ligands with beta2gpI. In the development of suitable conditions for analysis at neutral pH of this basic protein (pI about 8) we found the pH hysteresis behavior of fused silica surfaces useful since the protonated surface after an acid pre-wash counteracted protein adsorption efficiently in contrast to more laborious procedures including acrylamide/dimethylacrylamide coatings that did not permit analysis of this particular protein. This simple approach made estimates of heparin-beta2gpI interactions possible and the principle was shown also to work for detection of betagpI binding to anionic phospholipids. Utilizing the pH hysteresis effect may be a simple solution to the adsorption problems often encountered in analyses of proteins by CE.     

Thermodynamic quantities for the interaction of SO 4 2− with H+ and Na+ in aqueous solution from 150 to 320°C

The aqueous reactions,

Control of lysine reactivity in four-helix bundle proteins by site-selective pKa depression: expanding the versatility of proteins by postsynthetic functionalization

Five 42-residue polypeptides have been designed to fold into hairpin helix-loop-helix motifs that dimerize to form four-helix bundles, and to serve as protein scaffolds for the elucidation at the molecular level of the principles that control and fine-tune lysine and ornithine reactivities in a protein context. Site-selective control of Lys and Orn reactivity provides a mechanism for addressing directly individual residues and is a prerequisite for the site-selective functionalization of folded proteins. Several lysine and one ornithine residues were introduced on the surface and in the hydrophobic core of the folded motif. The reactivity of each residue was determined by measuring the degree of acylation of the trypsin cleaved fragments by HPLC and mass spectrometry. The most reactive residues were Orn34 and Lys19, both of which were located in d positions in the heptad repeat, and therefore in hydrophobic environments. Upon reaction of the helix-loop-helix dimer KA-I with one equivalent of mono-p-nitrophenyl fumarate, Orn34 was acylated approximately three times more efficiently than Lys19, whereas Lys10 (b position), Lys15 (g position), and Lys33 (c position) remained unmodified. In the sequence KA-I-A(15) Lys15 was replaced by an alanine residue and the selectivity of Orn34 over Lys19 increased to approximately a factor of six, probably because Lys15 had the capacity to reduce the pK(a) value of Lys19 and 85 % of site-selectively monoacylated product was obtained. The pH dependence of the acylation reaction was determined and showed that the pK(a) of the reactive residues were 9.3, more than a pK(a) unit below the magnitude of the corresponding residue in a solvent exposed position. Introducing Lys and Orn residues into a or d positions of the heptad repeat therefore serves as a mechanism of depressing their pK(a) to increase their reactivity site selectively. Extensive NMR and CD spectroscopic analyses showed that the sequences fold according to prediction.     

Dynamic alterations of fibronectin layers on copolymer substrates with graded physicochemical characteristics

Desorption and exchange of preadsorbed fibronectin layers in pure buffer solution and solutions of human serum albumin or fibronectin, respectively, were studied in dependence on the physicochemical characteristics of maleic acid copolymer films used as substrates. Although the preadsorbed amount of fibronectin differed only slightly, the protein was found to exhibit a significantly enhanced anchorage at the more hydrophobic polymer surface as compared to the more hydrophilic and more negatively charged polymer surface. The preadsorbed fibronectin layer was most efficiently exchanged by fibronectin (i.e., in the homodisplacement process) while pure buffer solution and human serum albumin solutions induced desorption or exchange of fibronectin to lower and similar degrees. An increase of the total adsorbed amount of protein due to additional adsorption of fibronectin or human serum albumin accompanied the partial exchange of the preadsorbed fibronectin in the displacement experiments. Evaluation of the kinetics of desorption and exchange of fibronectin at any of the substrates revealed two kinds of surface-attached protein populations--a fast desorbing species and a species with a slow desorption and exchange rate. By a multivariate regression analysis the surface characteristics of the polymer substrate were confirmed to determine the degree of protein desorption and exchange while the dynamics of the layer alteration was found to solely depend on the diffusion behavior of the proteins.     

Determination of Fibre Pore Structure: Influence of Salt,pH and Conventional Wet Strength Resins

It has been shown, in the present investigation, that the two methods used to investigate the pore size distribution of unbleached chemical pulps, i.e. inverse size exclusion chromatography (ISEC) and nuclear magnetic resonance (NMR), give different average pore radius for the pores inside the fibre wall. This is due to the way in which these experiments are performed and the sensitivity of the methods to different types of pores in the cell wall. It was also shown that the two methods gave different results when changing the pH and the ionic strength of the pulp suspension. The pore radius, as detected with ISEC, decreased with both increasing ionic strength and decreasing pH, indicating a loose structure of the exterior of the fibrillar network. However, the pore radius as detected with NMR, was virtually unaffected when increasing the ionic strength, indicating a very rigid structure of the interior of the fibre wall. Decreasing pH though, lead to a decrease in pore radius indicating that upon protonation of the carboxylic groups in the fibre wall, the electrostatic repulsion is diminished and the average pore radius decreases. The NMR technique was also used to study wet strength aid penetration into the fibre wall. It was shown that wet strength aids with a small molecular weight, penetrated the fibre wall, as detected by a decrease in pore radius. It was also shown that addition of different wet strength aids increased the tensile index of the sheet and decreased the fibre strength, measured as zero span-strength of the sheets.     

Preparation and redox properties of N,N,N-1,3,5-trialkylated flavin derivatives and their activity as redox catalysts

Eight different flavin derivatives have been synthesized and the electronic effects of substituents in various positions on the flavin redox chemistry were investigated. The redox potentials of the flavins, determined by cyclic voltammetry, correlated with their efficiency as catalysts in the H2O2 oxidation of methyl p-tolyl sulfide. Introduction of electron-withdrawing groups increased the stability of the reduced catalyst precursor.