Supercomputer-Based Ensemble Docking Drug Discovery Pipeline with Application to Covid-19.

We present a supercomputer-driven pipeline for in silico drug discovery using enhanced sampling molecular dynamics (MD) and ensemble docking. Ensemble docking makes use of MD results by docking compound databases into representative protein binding-site conformations, thus taking into account the dynamic properties of the binding sites. We also describe preliminary results obtained for 24 systems involving eight proteins of the proteome of SARS-CoV-2. The MD involves temperature replica exchange enhanced sampling, making use of massively parallel supercomputing to quickly sample the configurational space of protein drug targets. Using the Summit supercomputer at the Oak Ridge National Laboratory, more than 1 ms of enhanced sampling MD can be generated per day. We have ensemble docked repurposing databases to 10 configurations of each of the 24 SARS-CoV-2 systems using AutoDock Vina. Comparison to experiment demonstrates remarkably high hit rates for the top scoring tranches of compounds identified by our ensemble approach. We also demonstrate that, using Autodock-GPU on Summit, it is possible to perform exhaustive docking of one billion compounds in under 24 h. Finally, we discuss preliminary results and planned improvements to the pipeline, including the use of quantum mechanical (QM), machine learning, and artificial intelligence (AI) methods to cluster MD trajectories and rescore docking poses.

Prospects and challenges of iron pyroelectrolysis in magnesium aluminosilicate melts near minimum liquidus temperature.

Although steel production by molten oxide electrolysis offers potential economic and environmental advantages over classic extractive metallurgy, its feasibility is far from being convincingly demonstrated, mainly due to inherent experimental difficulties exerted by harsh conditions and lack of knowledge regarding relevant mechanisms and physico-chemical processes in the melts. The present work was intended to demonstrate the concept of pyroelectrolysis at very high temperature near the minimum liquidus point of magnesium aluminosilicate, being conducted under electron-blocking conditions using yttria-stabilized zirconia cells, and to provide a new insight into electrochemistry behind this process. Significant current yields are possible for pyroelectrolysis performed in electron-blocking mode using a solid electrolyte membrane to separate the anode and the molten electrolyte. Parasitic electrochemical processes rise gradually as the concentration of iron oxide dissolved in the molten electrolytes is depleted, impairing faradaic efficiency. Reduction of silica to metallic silicon was identified as a significant contribution to those parasitic currents, among other plausible processes. Direct pyroelectrolysis without electron blocking was found much less plausible, due to major limitations on faradaic efficiency imposed by electronic leakage and insufficient ionic conductivity of the aluminosilicate melt. Ohmic losses may consume an excessive fraction of the applied voltage, thus failing to sustain the Nernst potential required for reduction to metallic iron. The results suggest the need for further optimization of the molten electrolyte composition to promote ionic conductivity and to suppress electronic transport contribution, possibly, by tuning the Al/Si ratio and altering the network-forming/modifying behaviour of the iron cations.

Towards a high thermoelectric performance in rare-earth substituted SrTiO3: effects provided by strongly-reducing sintering conditions.

Donor-substituted strontium titanate ceramics demonstrate one of the most promising performances among n-type oxide thermoelectrics. Here we report a marked improvement of the thermoelectric properties in rare-earth substituted titanates Sr0.9R0.1TiO3±Î´ (R = La, Ce, Pr, Nd, Sm, Gd, Dy, Y) to achieve maximal ZT values of as high as 0.42 at 1190 K < T < 1225 K, prepared via a conventional solid state route followed by sintering under strongly reducing conditions (10%H2-90%N2, 1773 K). As a result of complex defect chemistry, both electrical and thermal properties were found to be dependent on the nature of the rare-earth cation and exhibit an apparent correlation with the unit cell size. High power factors of 1350-1550 µW m(-1) K(-2) at 400-550 K were observed for R = Nd, Sm, Pr and Y, being among the largest reported so far for n-type conducting bulk-ceramic SrTiO3-based materials. Attractive ZT values at high temperatures arise primarily from low thermal conductivity, which, in turn, stem from effective phonon scattering in oxygen-deficient perovskite layers formed upon reduction. The results suggest that highly-reducing conditions are essential and should be employed, whenever possible, in other related micro/nanostructural engineering approaches to suppress the thermal conductivity in target titanate-based ceramics.

Preliminary joint neutron time-of-flight and X-ray crystallographic study of human ABO(H) blood group A glycosyltransferase.

The biosyntheses of oligosaccharides and glycoconjugates are conducted by glycosyltransferases. These extraordinarily diverse and widespread enzymes catalyze the formation of glycosidic bonds through the transfer of a monosaccharide from a donor molecule to an acceptor molecule, with the stereochemistry about the anomeric carbon being either inverted or retained. Human ABO(H) blood group A α-1,3-N-acetylgalactosaminyltransferase (GTA) generates the corresponding antigen by the transfer of N-acetylgalactosamine from UDP-GalNAc to the blood group H antigen. To understand better how specific active-site-residue protons and hydrogen-bonding patterns affect substrate recognition and catalysis, neutron diffraction studies were initiated at the Protein Crystallography Station (PCS) at Los Alamos Neutron Science Center (LANSCE). A large single crystal was subjected to H/D exchange prior to data collection and time-of-flight neutron diffraction data were collected to 2.5 Šresolution at the PCS to ∼85% overall completeness, with complementary X-ray diffraction data collected from a crystal from the same drop and extending to 1.85 Šresolution. Here, the first successful neutron data collection from a glycosyltransferase is reported.

Enzymes for carbon sequestration: neutron crystallographic studies of carbonic anhydrase.

Carbonic anhydrase (CA) is a ubiquitous metalloenzyme that catalyzes the reversible hydration of CO(2) to form HCO(3)(-) and H(+) using a Zn-hydroxide mechanism. The first part of catalysis involves CO(2) hydration, while the second part deals with removing the excess proton that is formed during the first step. Proton transfer (PT) is thought to occur through a well ordered hydrogen-bonded network of waters that stretches from the metal center of CA to an internal proton shuttle, His64. These waters are oriented and ordered through a series of hydrogen-bonding interactions to hydrophilic residues that line the active site of CA. Neutron studies were conducted on wild-type human CA isoform II (HCA II) in order to better understand the nature and the orientation of the Zn-bound solvent (ZS), the charged state and conformation of His64, the hydrogen-bonding patterns and orientations of the water molecules that mediate PT and the ionization of hydrophilic residues in the active site that interact with the water network. Several interesting and unexpected features in the active site were observed which have implications for how PT proceeds in CA.

Preliminary neutron and X-ray crystallographic studies of equine cyanomethemoglobin.

Room-temperature and 100 K X-ray and room-temperature neutron diffraction data have been measured from equine cyanomethemoglobin to 1.7 A resolution using a home source, to 1.6 A resolution on NE-CAT at the Advanced Photon Source and to 2.0 A resolution on the PCS at Los Alamos Neutron Science Center, respectively. The cyanomethemoglobin is in the R state and preliminary room-temperature electron and neutron scattering density maps clearly show the protonation states of potential Bohr groups. Interestingly, a water molecule that is in the vicinity of the heme group and coordinated to the distal histidine appears to be expelled from this site in the low-temperature structure.

Preliminary joint neutron and X-ray crystallographic study of human carbonic anhydrase II.

Carbonic anhydrases catalyze the interconversion of CO(2) to HCO(3)(-), with a subsequent proton-transfer (PT) step. PT proceeds via a proposed hydrogen-bonded water network in the active-site cavity that is stabilized by several hydrophilic residues. A joint X-ray and neutron crystallographic study has been initiated to determine the specific water network and the protonation states of the hydrophilic residues that coordinate it in human carbonic anhydrase II. Time-of-flight neutron crystallographic data have been collected from a large ( approximately 1.2 mm(3)) hydrogen/deuterium-exchanged crystal to 2.4 A resolution and X-ray crystallographic data have been collected from a similar but smaller crystal to 1.5 A resolution. Obtaining good-quality neutron data will contribute to the understanding of the catalytic mechanisms that utilize water networks for PT in protein environments.

Preliminary time-of-flight neutron diffraction study of human deoxyhemoglobin.

Human hemoglobin (HbA) is an intricate system that has evolved to efficiently transport oxygen molecules (O(2)) from lung to tissue. Its quaternary structure can fluctuate between two conformations, T (tense or deoxy) and R (relaxed or oxy), which have low and high affinity for O(2), respectively. The binding of O(2) to the heme sites of HbA is regulated by protons and by inorganic anions. In order to investigate the role of the protonation states of protein residues in O(2) binding, large crystals of deoxy HbA (approximately 20 mm(3)) were grown in D(2)O under anaerobic conditions for neutron diffraction studies. A time-of-flight neutron data set was collected to 1.8 A resolution on the Protein Crystallography Station (PCS) at the spallation source run by Los Alamos Neutron Science Center (LANSCE). The HbA tetramer (64.6 kDa; 574 residues excluding the four heme groups) occupies the largest asymmetric unit (space group P2(1)) from which a high-resolution neutron data set has been collected to date.

Unusual redox behaviour of the magnetite/hematite core-shell structures processed by the laser floating zone method.

Magnetite (Fe3O4) offers unique physical and chemical properties, being an important material for many industrial applications. Certain limitations on the application conditions are, however, imposed by the redox stability issue. Fine control of the iron oxidation states represents a challenge for materials engineering. The present work explores relevant redox processes in iron oxides, processed under highly non-equilibrium laser floating zone (LFZ) conditions under atmospheres with different oxygen activities. The as-grown fibres showed a structure composed of the Fe3O4 core and the Fe2O3 shell. This study uncovers unexpectedly lower hematite content and shell thickness for the fibres processed under more oxidizing conditions. Combined structural and microstructural studies, supported by the analysis of the existing literature data, strongly suggest that the redox processes during the LFZ process can be rather determined by kinetics of melt crystallization, nuclei formation and heat transfer than by the oxygen content in the gas phase. The proposed mechanisms are further confirmed by electrical and magnetic studies of the composite fibres.

A suite-level review of the neutron single-crystal diffraction instruments at Oak Ridge National Laboratory.

The nascent suite of single-crystal neutron diffractometers at the Oak Ridge National Laboratory has no equal at any other neutron scattering facility worldwide and offers the potential to re-assert single-crystal diffraction using neutrons as a significant tool to study nuclear and magnetic structures of small unit cell crystals, nuclear structures of macromolecules, and diffuse scattering. Signature applications and features of single-crystal neutron diffraction are high resolution nuclear structure analysis, magnetic structure and spin density determinations, contrast variation (particularly D2O/H2O) for nuclear structural studies, lack of radiation damage when using crystals of biological molecules such as proteins, and the fidelity to measure nuclear and magnetic diffuse scattering with elastic discrimination.