Hit Expansion of a Noncovalent SARS-CoV-2 Main Protease Inhibitor.

Inhibition of the SARS-CoV-2 main protease (M) is a major focus of drug discovery efforts against COVID-19. Here we report a hit expansion of non-covalent inhibitors of M. Starting from a recently discovered scaffold (The COVID Moonshot Consortium.

Reduced Density Matrix-Driven Complete Active Apace Self-Consistent Field Corrected for Dynamic Correlation from the Adiabatic Connection.

The recently proposed multireference adiabatic connection (AC) formalism [Pernal, 120, 013001 (2018)] is applied to recover dynamic electron correlation effects lacking in variational two-electron reduced density matrix (v2RDM)-driven complete active space self-consistent field theory (CASSCF). The AC approach is validated by computing potential energy curves for the dissociation of molecular nitrogen and the symmetric double dissociation of HO while enforcing two sets of approximate -representability conditions in the underlying v2RDM-driven CASSCF calculations (either two-particle or two-particle plus partial three-particle conditions). The AC yields smaller absolute errors than second-order -electron perturbation theory (NEVPT2) at all molecular geometries for both sets of the -representability conditions considered.

Radical Dimerization in a Plastic Organic Crystal Leads to Structural and Magnetic Bistability with Wide Thermal Hysteresis.

The nitroxyl radical 1-methyl-2-azaadamantane -oxyl (Me-AZADO) exhibits magnetic bistability arising from a radical/dimer interconversion. The transition from the rotationally disordered paramagnetic plastic crystal, Me-AZADO, to the ordered diamagnetic crystalline phase, (Me-AZADO), has been conclusively demonstrated by crystal structure determination from high-resolution powder diffraction data and by solid-state NMR spectroscopy. The phase change is characterized by a wide thermal hysteresis with high sensitivity to even small applied pressures.

Heterogeneous CPU + GPU Algorithm for Variational Two-Electron Reduced-Density Matrix-Driven Complete Active-Space Self-Consistent Field Theory.

We present a heterogeneous central processing unit (CPU) + graphical processing unit (GPU) algorithm for the direct variational optimization of the two-electron reduced-density matrix (2RDM) under two-particle -representability conditions. This variational 2RDM (v2RDM) approach is the driver for a polynomially scaling approximation to configuration-interaction-driven complete active-space self-consistent field (CASSCF) theory. For v2RDM-based CASSCF computations involving an active space consisting of 50 electrons in 50 orbitals, we observe a speedup of a factor of 3.

Modeling core-level excitations with variationally optimized reduced-density matrices and the extended random phase approximation.

The information contained within ground-state one- and two-electron reduced-density matrices (RDMs) can be used to compute wave functions and energies for electronically excited states through the extended random phase approximation (ERPA). The ERPA is an appealing framework for describing excitations out of states obtained via the variational optimization of the two-electron RDM (2-RDM), as the variational 2-RDM (v2RDM) approach itself can only be used to describe the lowest-energy state of a given spin symmetry. The utility of the ERPA for predicting near-edge features relevant to x-ray absorption spectroscopy is assessed for the case that the 2-RDM is obtained from a ground-state v2RDM-driven complete active space self-consistent field (CASSCF) computation.

Analytic Energy Gradients for Variational Two-Electron Reduced-Density-Matrix-Driven Complete Active Space Self-Consistent Field Theory.

Analytic energy gradients are presented for a variational two-electron reduced-density-matrix (2-RDM)-driven complete active space self-consistent field (CASSCF) method. The active-space 2-RDM is determined using a semidefinite programing (SDP) algorithm built upon an augmented Lagrangian formalism. Expressions for analytic gradients are simplified by the fact that the Lagrangian is stationary with respect to variations in both the primal and the dual solutions to the SDP problem.