CHARMM at 45: Enhancements in Accessibility, Functionality, and Speed.

Since its inception nearly a half century ago, CHARMM has been playing a central role in computational biochemistry and biophysics. Commensurate with the developments in experimental research and advances in computer hardware, the range of methods and applicability of CHARMM have also grown. This review summarizes major developments that occurred after 2009 when the last review of CHARMM was published.

Obtaining QM/MM binding free energies in the SAMPL8 drugs of abuse challenge: indirect approaches.

Accurately predicting free energy differences is essential in realizing the full potential of rational drug design. Unfortunately, high levels of accuracy often require computationally expensive QM/MM Hamiltonians. Fortuitously, the cost of employing QM/MM approaches in rigorous free energy simulation can be reduced through the use of the so-called "indirect" approach to QM/MM free energies, in which the need for QM/MM simulations is avoided via a QM/MM "correction" at the classical endpoints of interest.

Tuaimenal A, a Meroterpene from the Irish Deep-Sea Soft Coral , Displays Inhibition of the SARS-CoV-2 3CLpro Enzyme.

Cold water benthic environments are a prolific source of structurally diverse molecules with a range of bioactivities against human disease. Specimens of a previously chemically unexplored soft coral, , were collected during a deep-sea cruise that sampled marine invertebrates along the Irish continental margin in 2018. Tuaimenal A (), a cyclized merosesquiterpenoid representing a new carbon scaffold with a highly substituted chromene core, was discovered through exploration of the soft coral secondary metabolome via NMR-guided fractionation.

CIFDock: A novel CHARMM-based flexible receptor-flexible ligand docking protocol.

Docking studies play a critical role in the current workflow of drug discovery. However, limitations may often arise through factors including inadequate ligand sampling, a lack of protein flexibility, scoring function inadequacies (e.g.

The Good, the Bad, and the Ugly: "HiPen", a New Dataset for Validating (S)QM/MM Free Energy Simulations.

Indirect (S)QM/MM free energy simulations (FES) are vital to efficiently incorporating sufficient sampling and accurate (QM) energetic evaluations when estimating free energies of practical/experimental interest. Connecting between levels of theory, i.e.