MiMiCPy: An Efficient Toolkit for MiMiC-Based QM/MM Simulations.

MiMiC is a highly flexible, extremely scalable multiscale modeling framework. It couples the CPMD (quantum mechanics, QM) and GROMACS (molecular mechanics, MM) codes. The code requires preparing separate input files for the two programs with a selection of the QM region. This can be a tedious procedure prone to human error, especially when dealing with large QM regions. Here, we present MiMiCPy, a user-friendly tool that automatizes the preparation of MiMiC input files. It is written in Python 3 with an object-oriented approach. The main subcommand PrepQM can be used to generate MiMiC inputs directly from the command line or through a PyMOL/VMD plugin for visually selecting the QM region. Many other subcommands are also provided for debugging and fixing MiMiC input files. MiMiCPy is designed with a modular structure that allows seamless extensions to new program formats depending on the requirements of MiMiC.

Molecular Dynamics and Structural Studies of Zinc Chloroquine Complexes.

Chloroquine (CQ) is a first-choice drug against malaria and autoimmune diseases. It has been co-administered with zinc against SARS-CoV-2 and soon dismissed because of safety issues. The structural features of Zn-CQ complexes and the effect of CQ on zinc distribution in cells are poorly known. In this study, state-of-the-art computations combined with experiments were leveraged to solve the structural determinants of zinc-CQ interactions in solution and the solid state. NMR, ESI-MS, and X-ray absorption and diffraction methods were combined with ab initio molecular dynamics calculations to address the kinetic lability of this complex. Within the physiological pH range, CQ binds Zn2+ through the quinoline ring nitrogen, forming [Zn(CQH)Clx(H2O)3-x](3+)-x (x = 0, 1, 2, and 3) tetrahedral complexes. The Zn(CQH)Cl3 species is stable at neutral pH and at high chloride concentrations typical of the extracellular medium, but metal coordination is lost at a moderately low pH as in the lysosomal lumen. The pentacoordinate complex [Zn(CQH)(H2O)4]3+ may exist in the absence of chloride. This in vitro/in silico approach can be extended to other metal-targeting drugs and bioinorganic systems.