CHARMM-GUI QM/MM Interfacer for a Quantum Mechanical and Molecular Mechanical (QM/MM) Simulation Setup: 1. Semiempirical Methods.

Quantum mechanical (QM) treatments, when combined with molecular mechanical (MM) force fields, can effectively handle enzyme-catalyzed reactions without significantly increasing the computational cost. In this context, we present CHARMM-GUI QM/MM Interfacer, a web-based cyberinfrastructure designed to streamline the preparation of various QM/MM simulation inputs with ligand modification. The development of QM/MM Interfacer has been achieved through integration with existing CHARMM-GUI modules, such as PDB Reader and Manipulator, Solution Builder, and Membrane Builder. In addition, new functionalities have been developed to facilitate the one-stop preparation of QM/MM systems and enable interactive and intuitive ligand modifications and QM atom selections. QM/MM Interfacer offers support for a range of semiempirical QM methods, including AM1(+/d), PM3(+/PDDG), MNDO(+/d, +/PDDG), PM6, RM1, and SCC-DFTB, tailored for both AMBER and CHARMM. A nontrivial setup related to ligand modification, link-atom insertion, and charge distribution is automatized through intuitive user interfaces. To illustrate the robustness of QM/MM Interfacer, we conducted QM/MM simulations of three enzyme-substrate systems: dihydrofolate reductase, insulin receptor kinase, and oligosaccharyltransferase. In addition, we have created three tutorial videos about building these systems, which can be found at https://www.charmm-gui.org/demo/qmi. QM/MM Interfacer is expected to be a valuable and accessible web-based tool that simplifies and accelerates the setup process for hybrid QM/MM simulations.

Directional molecular transport in iron redox flow batteries by interfacial electrostatic forces.

The mounting global energy demand urges surplus electricity generation. Due to dwindling fossil resources and environmental concerns, shifting from carbon-based fuels to renewables is vital. Though renewables are affordable, their intermittent nature poses supply challenges. In these contexts, aqueous flow batteries (AFBs), are a viable energy storage solution. This study tackles AFBs' energy density and efficiency challenges. Conventional strategies focus on altering molecule's solubility but overlook interface's transport kinetics. We show that triggering electrostatic forces at the interface can significantly enhance the mass transport kinetics of redox active molecules by introducing a powerful electrostatic flux over the diffusional flux, thereby exerting a precise directionality on the molecular transport. This approach of controlling the directionality of molecular flux in an all iron redox flow battery amplifies the current and power rating with approximately 140 % enhancement in the energy density.

Elucidating Dynamics of Adenylate Kinase from Enzyme Opening to Ligand Release.

This study explores ligand-driven conformational changes in adenylate kinase (AK), which is known for its open-to-close conformational transitions upon ligand binding and release. By utilizing string free energy simulations, we determine the free energy profiles for both enzyme opening and ligand release and compare them with profiles from the apoenzyme. Results reveal a three-step ligand release process, which initiates with the opening of the adenosine triphosphate-binding subdomain (ATP lid), followed by ligand release and concomitant opening of the adenosine monophosphate-binding subdomain (AMP lid). The ligands then transition to nonspecific positions before complete dissociation. In these processes, the first step is energetically driven by ATP lid opening, whereas the second step is driven by ATP release. In contrast, the AMP lid opening and its ligand release make minor contributions to the total free energy for enzyme opening. Regarding the ligand binding mechanism, our results suggest that AMP lid closure occurs via an induced-fit mechanism triggered by AMP binding, whereas ATP lid closure follows conformational selection. This difference in the closure mechanisms provides an explanation with implications for the debate on ligand-driven conformational changes of AK. Additionally, we determine an X-ray structure of an AK variant that exhibits significant rearrangements in the stacking of catalytic arginines, explaining its reduced catalytic activity. In the context of apoenzyme opening, the sequence of events is different. Here, the AMP lid opens first while the ATP lid remains closed, and the free energy associated with ATP lid opening varies with orientation, aligning with the reported AK opening and closing rate heterogeneity. Finally, this study, in conjunction with our previous research, provides a comprehensive view of the intricate interplay between various structural elements, ligands, and catalytic residues that collectively contribute to the robust catalytic power of the enzyme.