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. They include the following: new faster simulation engines, accessible user interfaces for convenient workflows, and a vast array of simulation and analysis methods that encompass quantum mechanical, atomistic, and coarse-grained levels, as well as extensive coverage of force fields. In addition to providing the current snapshot of the CHARMM development, this review may serve as a starting point for exploring relevant theories and computational methods for tackling contemporary and emerging problems in biomolecular systems. CHARMM is freely available for academic and nonprofit research at https://academiccharmm.org/program.

Significance: F ₁ -ATPase is a motor protein that converts the free energy of binding of ATP and its hydrolysis products ADP and P _i into a mechanical force for γ-subunit rotation. It is the catalytic moiety of F _o F ₁ -ATPase, which synthesizes ATP. There are two metastable states along each 120° rotation of the γ-subunit, one associated with ATP hydrolysis (the “catalytic dwell”) and the other with ATP binding (the “ATP waiting dwell”). We use molecular simulations to determine the ATP waiting dwell structure. With this structure and the catalytic dwell X-ray structure, we develop an atomic-level model of the coupling between ATP hydrolysis and γ-subunit rotation. The molecular-level understanding of this motor will aid in its use in nanomachines and cancer therapy.

An efficient and accurate reference potential simulation protocol is proposed for producing ab initio quantum mechanical/molecular mechanical (AI-QM/MM) quality free energy profiles for chemical reactions in a solvent or macromolecular environment. This protocol involves three stages: (a) using force matching to recalibrate a semi-empirical quantum mechanical (SE-QM) Hamiltonian for the specific reaction under study; (b) employing the recalibrated SE-QM Hamiltonian (in combination with molecular mechanical force fields) as the reference potential to drive umbrella samplings along the reaction pathway; and (c) computing AI-QM/MM energy values for collected configurations from the sampling and performing weighted thermodynamic perturbation to acquire an AI-QM/MM corrected reaction free energy profile. For three model reactions (identity S_N2 reaction, Menshutkin reaction, and glycine proton transfer reaction) in aqueous solution and one enzyme reaction (Claisen arrangement in chorismate mutase), our simulations using recalibrated PM3 SE-QM Hamiltonians well reproduced QM/MM free energy profiles at the B3LYP/6-31G* level of theory all within 1 kcal mol⁻¹ with a 20 to 45 fold reduction in the computer time.