BasisOpt: A Python package for quantum chemistry basis set optimization.

The accuracy and efficiency of molecular quantum chemical calculations depend critically on the basis set used. However, the development of novel basis sets is hindered because much of the literature relies on the use of opaque processes and tools that are not publicly available. We present here BasisOpt, a tool for the automated optimization of basis sets with an easy-to-use framework. It features an open and accessible workflow for basis set optimization that can be easily adapted to almost any quantum chemistry program, a standardized approach to testing basis sets, and visualization of both the optimized basis sets and the optimization process. We provide examples of usage in realistic basis set optimization scenarios where: (i) a density fitting basis set is optimized for He, Ne, and Ar; (ii) the exponents of the def2-SVP basis are re-optimized for a set of molecules rather than atoms; and (iii) a large, almost saturated basis of sp primitives is automatically reduced to (10s5p) while achieving the lowest energy for such a basis set composition.

Advancing structural biology through breakthroughs in AI.

The past century has witnessed an exponential increase in our atomic-level understanding of molecular and cellular mechanisms from a structural perspective, with multiple landmark achievements contributing to the field. This, coupled with recent and continuing breakthroughs in artificial intelligence methods such as AlphaFold2, and enhanced computational power, is enabling our understanding of protein structure and function at unprecedented levels of accuracy and predictivity. Here, we describe some of the major recent advances across these fields, and describe, as these technologies coalesce, the potential to utilise our enhanced knowledge of intricate cellular and molecular systems to discover novel therapeutics to alleviate human suffering.

Correlation consistent auxiliary basis sets in density fitting Hartree-Fock: The atoms sodium through argon revisited.

We present a series of auxiliary basis sets, for the elements Na to Ar, for use in density-fitted Hartree-Fock calculations with the correlation consistent cc-pV(n + d)Z orbital basis sets. Benchmarking on total molecular energies, reaction energies and the spectroscopic constants of the SO molecule demonstrate that the new sets address the deficiencies of using existing auxiliary sets in combination with these orbital basis sets. We also report auxiliary basis sets for Na and Mg matched to cc-pVnZ, along with recommendations for pairing auxiliary basis sets to the cc-pVnZ-F12 basis sets for Hartree-Fock calculations.

A first principles examination of phosphorescence.

This paper explores phosphorescence from a first principles standpoint, and examines the intricacies involved in calculating the spin-forbidden T 1 → S 0 transition dipole moment, to highlight that the mechanism is not as complicated to compute as it seems. Using gas phase acridine as a case study, we break down the formalism required to compute the phosphorescent spectra within both the Franck-Condon and Herzberg-Teller regimes by coupling the first triplet excited state up to the S 4 and T 4 states. Despite the first singlet excited state appearing as an L b state and not of nπ* character, the second order corrected rate constant was found to be 0.402 s-1, comparing well with experimental phosphorescent lifetimes of acridine derivatives. In showing only certain states are required to accurately describe the matrix elements as well as how to find these states, our calculations suggest that the nπ* state only weakly couples to the T 1 state. This suggest its importance hinges on its ability to quench fluorescence and exalt non-radiative mechanisms rather than its contribution to the transition dipole moment. A followup investigation into the T 1 → S 0 transition dipole moment's growth as a function of its coupling to other electronic states highlights that terms dominating the matrix element arise entirely from the inclusion of states with strong spin-orbit coupling terms. This means that while the expansion of the transition dipole moment can extend to include an infinite number of electronic states, only certain states need to be included.

Exciton Dynamics of a Diketo-Pyrrolopyrrole Core for All Low-Lying Electronic Excited States Using Density Functional Theory-Based Methods.

Ab initio treatments of interexcited state internal conversion (IC) are more often than not missing from exciton dynamic descriptions, because of their inherent complexity. Here, we define "interexcited state IC" as a same-spin nonradiative transition between states i and j, where i ≠ j ≠ 0. Competing directly with multiexciton processes such as singlet fission or triplet photoupconversion, inclusion of this mechanism in the narrative of molecular photophysics would allow for strategic synthesis of chromophores for more efficient photon-harvesting applications. Herein, we present a robust formalism which can model these rates using density functional theory (DFT)-based methods within the Franck-Condon and Herzberg-Teller regime. Using an unsubstituted diketo-pyrrolopyrrole (DPP) core as a case study, we illustrate the exciton dynamics along the first four excited states for both singlet and triplet manifolds, showing ultrafast same-spin transfer mechanisms due to all excited states, excluding the first triplet level, being in close energetic proximity (within 0.8 eV of each other). The resulting electron same-spin rates outcompete the electron spin-flipping intersystem crossing (ISC) rates, with excitons firmly obeying Kasha's rule as they cascade down from the high-lying excited states toward the lower states. Furthermore, we calculated that only the first singlet excited state displayed a reasonable probability of triplet exciton generation, of ∼40%, with a near-zero chance of the exciton reverting to the singlet manifold once the electron-hole pair are of parallel spin.

The quantum chemical solvation of indole: accounting for strong solute-solvent interactions using implicit/explicit models.

In this paper, we investigate the efficacy of different quantum chemical solvent modelling methods of indole in both water and methylcyclohexane solutions. The goal is to show that one can yield good photophysical properties in strongly coupled solute-solvent systems using standard DFT methods. We use standard and linearly-corrected Polarisable Continuum Models (PCM), as well as explicit solvation models, and compare the different model parameters, including the choice of density functional, basis set, and number of explicit solvent molecules. We demonstrate that implicit models overestimate energies and oscillator strengths. In particular, for indole-water, no level inversion is observed, suggesting a dielectric medium on its own is insufficient. In contrast, energies are seen to converge fairly rapidly with respect to cluster size towards experimentally measured properties in the explicit models. We find that the use of B3LYP with a diffuse basis set can adequately represent the photophysics of the system with a cluster size of between 9-12 explicit water molecules. Sampling of configurations from a molecular dynamics simulation suggests that the single point results are suitably representative of the solvated ensemble. For indole-water, we show that solvent reorganisation plays a significant role in stabilisation of the excited state energies. It is hoped that the findings and observations of this study will aid in the choice of solvation model parameters in future studies.

Correlation consistent basis sets for explicitly correlated wavefunctions: Pseudopotential-based basis sets for the group 11 (Cu, Ag, Au) and 12 (Zn, Cd, Hg) elements.

New correlation consistent basis sets for the group 11 (Cu, Ag, Au) and 12 (Zn, Cd, Hg) elements have been developed specifically for use in explicitly correlated F12 calculations. This includes orbital basis sets for valence only (cc-pVnZ-PP-F12, n = D, T, Q) and outer core-valence (cc-pCVnZ-PP-F12) correlation, along with both of these augmented with additional high angular momentum diffuse functions. Matching auxiliary basis sets required for density fitting and resolution-of-the-identity approaches to conventional and F12 integrals have also been optimized. All of the basis sets are to be used in conjunction with small-core relativistic pseudopotentials [Figgen et al., Chem. Phys. 311, 227 (2005)]. The accuracy of the basis sets is determined through benchmark calculation at the explicitly correlated coupled-cluster level of theory for various properties of atoms and diatomic molecules. The convergence of the properties with respect to the basis set is dramatically improved compared to conventional coupled-cluster calculations, with cc-pVTZ-PP-F12 results close to conventional estimates of the complete basis set limit. The patterns of convergence are also greatly improved compared to those observed from the use of conventional correlation consistent basis sets in F12 calculations.

Efficient enumeration of bosonic configurations with applications to the calculation of non-radiative rates.

This work presents algorithms for the efficient enumeration of configuration spaces following Boltzmann-like statistics, with example applications to the calculation of non-radiative rates, and an open-source implementation. Configuration spaces are found in several areas of physics, particularly wherever there are energy levels that possess variable occupations. In bosonic systems, where there are no upper limits on the occupation of each level, enumeration of all possible configurations is an exceptionally hard problem. We look at the case where the levels need to be filled to satisfy an energy criterion, for example, a target excitation energy, which is a type of knapsack problem as found in combinatorics. We present analyses of the density of configuration spaces in arbitrary dimensions and how particular forms of kernel can be used to envelope the important regions. In this way, we arrive at three new algorithms for enumeration of such spaces that are several orders of magnitude more efficient than the naive brute force approach. Finally, we show how these can be applied to the particular case of internal conversion rates in a selection of molecules and discuss how a stochastic approach can, in principle, reduce the computational complexity to polynomial time.

CHARMM-DYES: Parameterization of Fluorescent Dyes for Use with the CHARMM Force Field.

We present CHARMM-compatible force field parameters for a series of fluorescent dyes from the Alexa, Atto, and Cy families, commonly used in Förster resonance energy transfer (FRET) experiments. These dyes are routinely used in experiments to resolve the dynamics of proteins and nucleic acids at the nanoscale. However, little is known about the accuracy of the theoretical approximations used in determining the dynamics from the spectroscopic data. Molecular dynamics simulations can provide valuable insights into these dynamics at an atomistic level, but this requires accurate parameters for the dyes. The complex structure of the dyes and the importance of this in determining their spectroscopic properties mean that parameters generated by analogy to existing parameters do not give meaningful results. Through validation relative to quantum chemical calculation and experiments, the new parameters are shown to significantly outperform those that can be generated automatically, giving better agreement in both the charge distributions and structural properties. These improvements, in particular with regard to orientation of the dipole moments on the dyes, are vital for accurate simulation of FRET processes.

Computational Investigations of Dispersion Interactions between Small Molecules and Graphene-like Flakes.

We investigate dispersion interactions in a selection of atomic, molecular, and molecule-surface systems, comparing high-level correlated methods with empirically corrected density functional theory (DFT). We assess the efficacy of functionals commonly used for surface-based calculations, with and without the D3 correction of Grimme. We find that the inclusion of the correction is essential to get meaningful results, but there is otherwise little to distinguish between the functionals. We also present coupled-cluster quality interaction curves for H2, NO2, H2O, and Ar interacting with large carbon flakes, acting as models for graphene surfaces, using novel absolutely localized molecular orbital based methods. These calculations demonstrate that the problems with empirically corrected DFT when investigating dispersion appear to compound as the system size increases, with important implications for future computational studies of molecule-surface interactions.

Psi4 1.4: Open-source software for high-throughput quantum chemistry.

PSI4 is a free and open-source ab initio electronic structure program providing implementations of Hartree-Fock, density functional theory, many-body perturbation theory, configuration interaction, density cumulant theory, symmetry-adapted perturbation theory, and coupled-cluster theory. Most of the methods are quite efficient, thanks to density fitting and multi-core parallelism. The program is a hybrid of C++ and Python, and calculations may be run with very simple text files or using the Python API, facilitating post-processing and complex workflows; method developers also have access to most of PSI4's core functionalities via Python. Job specification may be passed using The Molecular Sciences Software Institute (MolSSI) QCSCHEMA data format, facilitating interoperability. A rewrite of our top-level computation driver, and concomitant adoption of the MolSSI QCARCHIVE INFRASTRUCTURE project, makes the latest version of PSI4 well suited to distributed computation of large numbers of independent tasks. The project has fostered the development of independent software components that may be reused in other quantum chemistry programs.

A Linear-Scaling Method for Noncovalent Interactions: An Efficient Combination of Absolutely Localized Molecular Orbitals and a Local Random Phase Approximation Approach.

A novel method for the accurate and efficient calculation of interaction energies in weakly bound complexes composed of a large number of molecules is presented. The new ALMO+RPAd method circumvents the prohibitive scaling of coupled cluster singles and doubles while still providing similar accuracy across a diverse range of weakly bound chemical systems. Linear-scaling procedures for the Fock build are given utilizing absolutely localized molecular orbitals (ALMOs), resulting in the a priori exclusion of basis set superposition errors. A bespoke data structure and algorithm using density fitting are described, leading to linear scaling for the storage and computation of the two-electron integrals. Electron correlation is included through a new, linear-scaling pairwise local random phase approximation approach, including exchange interactions, and decomposed into purely dispersive excitations (RPAxd). Collectively, these allow meaningful decomposition of the interaction energy into physically distinct contributions: electrostatic, polarization, charge transfer, and dispersion. Comparison with symmetry-adapted perturbation theory shows good qualitative agreement. Tests on various dimers and the S66 benchmark set demonstrate results within 0.5 kcal mol-1 of coupled cluster singles and doubles results. On a large cluster of water molecules, we achieve calculations involving over 3500 orbital and 12,000 auxiliary basis functions in under 10 min on a single CPU core.

Interplay between hydrogen bonding and n→π* interaction in an analgesic drug salicin.

The competition and cooperation between weak intermolecular interactions are important in determining the conformational preferences of molecules. Understanding the relative strengths of these effects in the context of potential drug candidates is therefore essential. We use a combination of gas-phase spectroscopy and quantum-chemical calculations to elucidate the nature of such interactions for the analgesic salicin [2-(hydroxymethyl)phenyl ß-d-glucopyranoside], an analog of aspirin found in willow bark. Of several possible conformers, only three are observed experimentally, and these are found to correspond with the three lowest energy conformers obtained from density functional theory calculations and simulated Franck-Condon spectra. Natural bond orbital analyses show that these are characterized by a subtle interplay between weak n→π* interaction and conventional strong hydrogen bond, with additional insights into this interaction provided by analysis of quantum theory of atoms in molecules and symmetry-adapted perturbation theory calculations. In contrast, the higher energy conformers, which are not observed experimentally, are mostly stabilized by the hydrogen bond with negligible contribution of n→π* interaction. The n→π* interaction results in a preference for the benzyl alcohol group of salicin to adopt a gauche conformation, a characteristic also found when salicin is bound to the ß-glucosidase enzyme. As such, understanding the interplay between these weak interactions has significance in the rationalization of protein structures.

Prescreening and efficiency in the evaluation of integrals over ab initio effective core potentials.

New, efficient schemes for the prescreening and evaluation of integrals over effective core potentials (ECPs) are presented. The screening is shown to give a rigorous, and close bound, to within on average 10% of the true value. A systematic rescaling procedure is given to reduce this error to approximately 0.1%. This is then used to devise a numerically stable recursive integration routine that avoids expensive quadratures. Tests with coupled clusters with single and double excitations and perturbative triple calculations on small silver clusters demonstrate that the new schemes show no loss in accuracy, while reducing both the power and prefactor of the scaling with system size. In particular, speedups of roughly 40 times can be achieved compared to quadrature-based methods.

Approaching the Hartree-Fock Limit through the Complementary Auxiliary Basis Set Singles Correction and Auxiliary Basis Sets.

Auxiliary basis sets for use in the resolution of the identity (RI) approximation in explicitly correlated methods are presented for the elements H-Ar. These extend the cc-pVnZ-F12/OptRI (n = D-Q) auxiliary basis sets of Peterson and co-workers by the addition of a small number of s- and p-functions, optimized so as to yield the greatest complementary auxiliary basis set (CABS) singles correction to the Hartree-Fock energy. The new sets, denoted OptRI+, also lead to a reduction in errors due to the RI approximation and hence an improvement in correlation energies. The atomization energies and heats of formation for a test set of small molecules, and spectroscopic constants for 27 diatomics, calculated at the CCSD(T)-F12b level, are shown to have improved error distributions for the new auxiliary basis sets with negligible additional effort. The OptRI+ sets retain all of the desirable properties of the original OptRI, including the production of smooth potential energy surfaces, while maintaining a compact nature.

Halogen Bonding with Phosphine: Evidence for Mulliken Inner Complexes and the Importance of Relaxation Energy.

Intermolecular halogen bonding in complexes of phosphine and dihalogens has been theoretically investigated using explicitly correlated coupled cluster methods and symmetry-adapted perturbation theory. The complexes H3P···ClF, H3P···BrF, and H3P···IF are demonstrated to possess unusually strong interactions that are accompanied by an increase in the induction component of the interaction energy and significant elongation of the X-Y halogen distance on complex formation. The combination of these factors is indicative of Mulliken inner complexes, and criteria for identifying this classification are further developed. The importance of choosing an electronic structure method that describes both dispersion and longer range interactions is demonstrated, along with the need to account for the change in geometry on complexation formation via relaxation energy and overall stabilization energies.

The Pre-Anschluss Vienna School of Medicine - The medical scientists: Karl Landsteiner (1868-1943) and Otto Loewi (1873-1961).

Two famous medical scientists are described whose major advances were made largely from laboratory-based research. Karl Landsteiner, who received the Nobel Prize in 1930, was the discoverer or co-discoverer of the blood groups and the Rhesus factor. He contributed to the understanding of poliomyelitis, syphilis and typhus. He made major contributions to immunology, inter alia by isolating haptens. After World War I, he left Austria and continued his work initially in the Netherlands and then at the Rockefeller Institute in the USA. Otto Loewi, a pharmacologist, received his Nobel Prize (jointly with his life-long friend, Sir Henry Dale) in 1936 for his discovery that acetylcholine was the chemical agent for the stimulation of autonomic nerves to transmit to the organs they govern. He also made numerous other contributions including the demonstration that amino acids could be converted by animals to proteins. He left Austria after the Anschluss and settled in the USA.

The pre-Anschluss Vienna School of Medicine - the physicians: Sigmund Freud (1856-1939), Julius Wagner-Jauregg (1857-1940) and Karel Wenckebach (1864-1940).

Three physicians are discussed. Sigmund Freud, probably the best-known member of the Vienna School of Medicine, was the path-breaking pioneer in psychoanalysis and psychotherapy. Julius Wagner-Jauregg was a psychiatrist who discovered the link between iodine deficiency and goitre and also developed malaria therapy to treat progressive paralysis caused by syphilis for which he was awarded the Nobel Prize. Karel Wenckebach, the pioneering Dutch cardiologist, is best known for the Wenckebach block. After the Anschluss, fate dealt very different hands to these three physicians. Freud fled to London where he soon died. Wagner-Jauregg, who had some pan-Germanic sympathies as well as views on eugenics, left a controversial legacy. The Dutch cardiologist Wenckebach died in Vienna shortly after his homeland had been invaded in 1940 by that of his hosts.

The Pre-Anschluss Vienna School of Medicine--The surgeons: Ignaz Semmelweis (1818-1865), Theodor Billroth (1829-1894) and Robert Bárány (1876-1936).

A brief history of the Vienna School of Medicine is sketched out from its founding in the mid-18th century by Gerard van Swieten until the Anschluss in March 1938. The pioneering work of Ignaz Semmelweis on the causes and the prevention of puerperal fever is discussed. This is followed by ground-breaking innovations, particularly in abdominal surgery, by Theodor Billroth and by Robert Bárány's Nobel Prize winning work inter alia on defining the pathology and physiology of the human vestibular apparatus. The lives and work of these three outstanding medical practitioners are described, together with their successes and failures. Only Billroth's achievements were appreciated in Vienna during their lifetimes. Semmelweis' work was belittled during his lifetime and he died obscurely in a mental institution. Bárány had to immigrate to Sweden to achieve recognition.

Fulminant hepatitis following chemotherapy treatment for breast cancer.

A woman in her early 50s was admitted to the intensive care unit with nausea, altered mental status and hepatic failure. She had a history of asymptomatic chronic hepatitis B and recently received chemotherapy for breast cancer. A diagnosis of hepatitis B reactivation (HBR) was made, but unfortunately she died of liver failure. Controversies around testing for hepatitis B prior to giving immunosuppressive treatments and the use of prophylactic antiviral therapy to prevent HBR are discussed.