Quantum Chemical Characterization of Rotamerism in Thio-Michael Additions for Targeted Covalent Inhibitors.

Myotonic dystrophy type I (DM1) is the most common form of adult muscular dystrophy and is a severe condition with no treatment currently available. Recently, small-molecule ligands have been developed as targeted covalent inhibitors that have some selectivity for and covalently inhibit cyclin-dependent kinase 12 (CDK12). CDK12 is involved in the transcription of elongated RNA sections that results in the DM1 condition.

An Improved Diabatization Scheme for Computing the Electronic Circular Dichroism of Proteins.

We advance the quality of first-principles calculations of protein electronic circular dichroism (CD) through an amelioration of a key deficiency of a previous procedure that involved diabatization of electronic states on the amide chromophore (to obtain interamide couplings) in a β-strand conformation of a diamide. This yields substantially improved calculated far-ultraviolet (far-UV) electronic circular dichroism (CD) spectra for β-sheet conformations. The interamide couplings from the diabatization procedure for 13 secondary structural elements (13 diamide structures) are applied to compute the CD spectra for seven example proteins: myoglobin (α helix), jacalin (β strand), concanavalin A (β type I), elastase (β type II), papain (α + β), 3-helix bundle (3-helix) and snow flea antifreeze protein (polyproline).

Modeling interactions between rubidium atom and magnetometer cell wall molecules.

Magnetometer cell wall coat molecules play an important role in preserving the lifetime of pumped alkali metal atoms for use in magnetometers that are capable of measuring very small magnetic fields. The goal of this study is to help rationalize the design of the cell coat molecules. Rubidium-87 is studied in terms of its interaction with three template cell coat molecules: ethane, ethene, and methyltrichlorosilane (MeTS).

A facile one step route that introduces functionality to polymer powders for laser sintering.

Laser Sintering (LS) is a type of Additive Manufacturing (AM) exploiting laser processing of polymeric particles to produce 3D objects. Because of its ease of processability and thermo-physical properties, polyamide-12 (PA-12) represents ~95% of the polymeric materials used in LS. This constrains the functionality of the items produced, including limited available colours.

Theoretical analysis of divalent cation effects on aptamer recognition of neurotransmitter targets.

Aptamer-based sensing of small molecules such as dopamine and serotonin in the brain, requires characterization of the specific aptamer sequences in solutions mimicking the environment with physiological ionic concentrations. In particular, divalent cations (Mg and Ca) present in brain fluid, have been shown to affect the conformational dynamics of aptamers upon target recognition. Thus, for biosensors that transduce aptamer structure switching as the signal response, it is critical to interrogate the influence of divalent cations on each unique aptamer sequence.

QuantumScents: Quantum-Mechanical Properties for 3.5k Olfactory Molecules.

Quantitative structure-odor relationships are critically important for studies related to the function of olfaction. Current literature data sets contain expert-labeled molecules but lack feature data. This paper introduces QuantumScents, a quantum mechanics augmented derivative of the Leffingwell data set.

SARS-CoV2 billion-compound docking.

This dataset contains ligand conformations and docking scores for 1.4 billion molecules docked against 6 structural targets from SARS-CoV2, representing 5 unique proteins: MPro, NSP15, PLPro, RDRP, and the Spike protein. Docking was carried out using the AutoDock-GPU platform on the Summit supercomputer and Google Cloud.

Cysteine-Selective Modification of Peptides and Proteins via Desulfurative C-C Bond Formation.

The site-selective modification of peptides and proteins facilitates the preparation of targeted therapeutic agents and tools to interrogate biochemical pathways. Among the numerous bioconjugation techniques developed to install groups of interest, those that generate C(sp )-C(sp ) bonds are significantly underrepresented despite affording proteolytically stable, biogenic linkages. Herein, a visible-light-mediated reaction is described that enables the site-selective modification of peptides and proteins via desulfurative C(sp )-C(sp ) bond formation.

Molecular basis for higher affinity of SARS-CoV-2 spike RBD for human ACE2 receptor.

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has caused substantially more infections, deaths, and economic disruptions than the 2002-2003 SARS-CoV. The key to understanding SARS-CoV-2's higher infectivity lies partly in its host receptor recognition mechanism. Experiments show that the human angiotensin converting enzyme 2 (ACE2) protein, which serves as the primary receptor for both CoVs, binds to the receptor binding domain (RBD) of CoV-2's spike protein stronger than SARS-CoV's spike RBD.

Near-Ultraviolet Circular Dichroism and Two-Dimensional Spectroscopy of Polypeptides.

A fully quantitative theory of the relationship between protein conformation and optical spectroscopy would facilitate deeper insights into biophysical and simulation studies of protein dynamics and folding. In contrast to intense bands in the far-ultraviolet, near-UV bands are much weaker and have been challenging to compute theoretically. We report some advances in the accuracy of calculations in the near-UV, which were realised through the consideration of the vibrational structure of the electronic transitions of aromatic side chains.

Protein Conformational States-A First Principles Bayesian Method.

Automated identification of protein conformational states from simulation of an ensemble of structures is a hard problem because it requires teaching a computer to recognize shapes. We adapt the naïve Bayes classifier from the machine learning community for use on atom-to-atom pairwise contacts. The result is an unsupervised learning algorithm that samples a 'distribution' over potential classification schemes.

Supercomputing Pipelines Search for Therapeutics Against COVID-19.

The urgent search for drugs to combat SARS-CoV-2 has included the use of supercomputers. The use of general-purpose graphical processing units (GPUs), massive parallelism, and new software for high-performance computing (HPC) has allowed researchers to search the vast chemical space of potential drugs faster than ever before. We developed a new drug discovery pipeline using the Summit supercomputer at Oak Ridge National Laboratory to help pioneer this effort, with new platforms that incorporate GPU-accelerated simulation and allow for the virtual screening of billions of potential drug compounds in days compared to weeks or months for their ability to inhibit SARS-COV-2 proteins.

Force Fields for Macromolecular Assemblies Containing Diketopyrrolopyrrole and Thiophene.

Utilizing a force-matching procedure, we parametrize new force fields systematically for large conjugated systems. We model both conjugated polymers and molecular crystals that contain diketopyrrolopyrrole, thiophene, and thieno[3,2-]thiophene units. These systems have recently been found to have low band gaps, which exhibit high efficiency for photovoltaic devices.

Dewar Benzenoids Discovered In Carbon Nanobelts.

The synthesis of cyclacene nanobelts remains an elusive goal dating back over 60 years. These molecules represent the last unsynthesized building block of carbon nanotubes and may be useful both as seed molecules for the preparation of structurally well-defined carbon nanotubes and for understanding the behavior and formation of zigzag nanotubes more broadly. Here we report the discovery that isomers containing two Dewar benzenoid rings are the preferred form for several sizes of cyclacene.

Hydration and Dispersion Forces in Hydroxypropylcellulose Phase Behavior.

Many-body polarization and hydration forces can strongly affect the equilibrium structure and energetics of mixed phases. Accurately reproducing both forces presents a challenge to force field models because it requires balancing hydrogen bonding at short range with many-body orientational order and dispersive attraction at long range. This work reports the first comparison of experimental measurements of the pressure-area isotherm for hydroxypropylcellulose (HPC) against molecular dynamics results with four different force field models-united-atom, all-atom (OPLS and CHARMM), and Drude oscillator models.

Ultrafast photodissociation dynamics of 1,4-diiodobenzene.

The photodissociation dynamics of 1,4-diiodobenzene is investigated using ultrafast time-resolved photoelectron spectroscopy. Following excitation by laser pulses at 271 nm, the excited-state dynamics is probed by resonance-enhanced multiphoton ionization with 405 nm probe pulses. A progression of Rydberg states, which come into resonance sequentially, provide a fingerprint of the dissociation dynamics of the molecule.

Accelerating QM/MM Free Energy Computations via Intramolecular Force Matching.

The calculation of free energy differences between levels of theory has numerous potential pitfalls. Chief among them is the lack of overlap, i.e.

Insertion of Dengue E into lipid bilayers studied by neutron reflectivity and molecular dynamics simulations.

The envelope (E) protein of Dengue virus rearranges to a trimeric hairpin to mediate fusion of the viral and target membranes, which is essential for infectivity. Insertion of E into the target membrane serves to anchor E and possibly also to disrupt local order within the membrane. Both aspects are likely to be affected by the depth of insertion, orientation of the trimer with respect to the membrane normal, and the interactions that form between trimer and membrane.

Extension of Kirkwood-Buff theory to the canonical ensemble.

Kirkwood-Buff (KB) integrals are notoriously difficult to converge from a canonical simulation because they require estimating the grand-canonical radial distribution. The same essential difficulty is encountered when attempting to estimate the direct correlation function of Ornstein-Zernike theory by inverting the pair correlation functions. We present a new theory that applies to the entire, finite, simulation volume, so that no cutoff issues arise at all.

Coherent ultrafast lattice-directed reaction dynamics of triiodide anion photodissociation.

Solid-state reactions are influenced by the spatial arrangement of the reactants and the electrostatic environment of the lattice, which may enable lattice-directed chemical dynamics. Unlike the caging imposed by an inert matrix, an active lattice participates in the reaction, however, little evidence of such lattice participation has been gathered on ultrafast timescales due to the irreversibility of solid-state chemical systems. Here, by lowering the temperature to 80 K, we have been able to study the dissociative photochemistry of the triiodide anion (I) in single-crystal tetra-n-butylammonium triiodide using broadband transient absorption spectroscopy.

Einstein-Podolsky-Rosen paradox implies a minimum achievable temperature.

This work examines the thermodynamic consequences of the repeated partial projection model for coupling a quantum system to an arbitrary series of environments under feedback control. This paper provides observational definitions of heat and work that can be realized in current laboratory setups. In contrast to other definitions, it uses only properties of the environment and the measurement outcomes, avoiding references to the "measurement" of the central system's state in any basis.

Ligand coordination modulates reductive elimination from aluminium(iii).

Oxidative addition of inert bonds at low-valent main-group centres is becoming a major class of reactivity for these species. The reverse reaction, reductive elimination, is possible in some cases but far rarer. Here, we present a mechanistic study of reductive elimination from Al(iii) centres and unravel ligand effects in this process.

Overcoming the minimum image constraint using the closest point search.

Finding the set of nearest images of a point in a simulation cell with periodic (torus) boundary conditions is of central importance for molecular dynamics algorithms. To compute all pairwise distances closer than a given cutoff in linear time requires region-based neighbor-listing algorithms. Available algorithms encounter increasing difficulties when the cutoff distance exceeds half the shortest cell length.