Recent Developments in Metal-Based Drugs and Chelating Agents for Neurodegenerative Diseases Treatments.

The brain has a unique biological complexity and is responsible for important functions in the human body, such as the command of cognitive and motor functions. Disruptive disorders that affect this organ, e.g. neurodegenerative diseases (NDDs), can lead to permanent damage, impairing the patients' quality of life and even causing death. In spite of their clinical diversity, these NDDs share common characteristics, such as the accumulation of specific proteins in the cells, the compromise of the metal ion homeostasis in the brain, among others. Despite considerable advances in understanding the mechanisms of these diseases and advances in the development of treatments, these disorders remain uncured. Considering the diversity of mechanisms that act in NDDs, a wide range of compounds have been developed to act by different means. Thus, promising compounds with contrasting properties, such as chelating agents and metal-based drugs have been proposed to act on different molecular targets as well as to contribute to the same goal, which is the treatment of NDDs. This review seeks to discuss the different roles and recent developments of metal-based drugs, such as metal complexes and metal chelating agents as a proposal for the treatment of NDDs.

Combining classical molecular dynamics and quantum mechanical methods for the description of electronic excitations: The case of carotenoids.

Carotenoids are important actors both in light-harvesting (LH) and in photoprotection functions of photosynthetic pigment-protein complexes. A deep theoretical investigation of this multiple role is still missing owing to the difficulty of describing the delicate interplay between electronic and nuclear degrees of freedom. A possible strategy is to combine accurate quantum mechanical (QM) methods with classical molecular dynamics. To do this, however, accurate force-fields (FF) are necessary. This article presents a new FF for the different carotenoids present in LH complexes of plants. The results show that all the important structural properties described by the new FF are in very good agreement with QM reference values. This increased accuracy in the simulation of the structural fluctuations is also reflected in the description of excited states. Both the energy order and the different nature of the lowest singlet states are preserved during the dynamics when the new FF is used, whereas an unphysical mixing is found when a standard FF is used.

Photoprotection and triplet energy transfer in higher plants: the role of electronic and nuclear fluctuations.

Photosynthetic organisms employ several photoprotection strategies to avoid damage due to the excess energy in high light conditions. Among these, quenching of triplet chlorophylls by neighboring carotenoids (Cars) is fundamental in preventing the formation of singlet oxygen. Cars are able to accept the triplets from chlorophylls by triplet energy transfer (TET). We have here studied TET rates in CP29, a minor light-harvesting complex (LHC) of the Photosystem II in plants. A fully atomistic strategy combining classical molecular dynamics of the LHC in its natural environment with a hybrid time-dependent density functional theory/polarizable MM description of the TET is used. We find that the structural fluctuations of the pigment-protein complex can largely enhance the transfer rates with respect to those predicted using the crystal structure, reducing the triplet quenching times in the subnanosecond scale. These findings add a new perspective for the interpretation of the photoprotection function and its relation with structural motions of the LHC.

Towards an ab initio description of the optical spectra of light-harvesting antennae: application to the CP29 complex of photosystem II.

Light-harvesting pigment-protein complexes (PPC) represent the fundamental units through which the photosynthetic organisms absorb sunlight and funnel the energy to the reaction centre for carrying out the primary energy conversion reactions of photosynthesis. Here we apply a multiscale computational strategy to a specific PPC present in the photosystem II of plants and algae (CP29) to investigate in what detail should the environment effects due to protein and membrane/solvent be included for an accurate description of optical spectra. We find that a refinement of the crystal structure is needed before any meaningful quantum chemical calculations of pigment transition energies can be performed. For this purpose we apply classical molecular dynamics simulations of the PPC within its natural environment and we perform ab initio computations of the exciton Hamiltonian of the complex, including the environment either implicitly by the polarizable continuum model (PCM) or explicitly using the polarizable QM/MM methodology (MMPol). However, PCM essentially leads to an unspecific redshift of all transition energies, and MMPol is able to reveal site-specific changes in the optical properties of the pigments. Based on the latter and the excitonic couplings obtained within a polarizable QM/MM methodology, optical spectra are calculated, which are in good qualitative agreement with experimental data. A weakness of the approach is however found in the overestimation of the fluctuations of the excitonic parameters of the pigments along the MD trajectory. An explanation for such a finding in terms of the limits of the force fields commonly used for protein cofactors is presented and discussed.

The SARS-CoV-2 spike protein binds and modulates estrogen receptors.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike (S) protein binds angiotensin-converting enzyme 2 (ACE2) at the cell surface, which constitutes the primary mechanism driving SARS-CoV-2 infection. Molecular interactions between the transduced S and endogenous proteins likely occur post-infection, but such interactions are not well understood. We used an unbiased primary screen to profile the binding of full-length S against >9,000 human proteins and found significant S-host protein interactions, including one between S and human estrogen receptor alpha (ERα). After confirming this interaction in a secondary assay, we used bioinformatics, supercomputing, and experimental assays to identify a highly conserved and functional nuclear receptor coregulator (NRC) LXD-like motif on the S2 subunit and an S-ERα binding mode. In cultured cells, S DNA transfection increased ERα cytoplasmic accumulation, and S treatment induced ER-dependent biological effects and ACE2 expression. Noninvasive multimodal PET/CT imaging in SARS-CoV-2-infected hamsters using [ 18 F]fluoroestradiol (FES) localized lung pathology with increased ERα lung levels. Postmortem experiments in lung tissues from SARS-CoV-2-infected hamsters and humans confirmed an increase in cytoplasmic ERα expression and its colocalization with S protein in alveolar macrophages. These findings describe the discovery and characterization of a novel S-ERα interaction, imply a role for S as an NRC, and are poised to advance knowledge of SARS-CoV-2 biology, COVID-19 pathology, and mechanisms of sex differences in the pathology of infectious disease.

The SARS-CoV-2 spike protein binds and modulates estrogen receptors.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike (S) protein binds angiotensin-converting enzyme 2 as its primary infection mechanism. Interactions between S and endogenous proteins occur after infection but are not well understood. We profiled binding of S against >9000 human proteins and found an interaction between S and human estrogen receptor α (ERα). Using bioinformatics, supercomputing, and experimental assays, we identified a highly conserved and functional nuclear receptor coregulator (NRC) LXD-like motif on the S2 subunit. In cultured cells, S DNA transfection increased ERα cytoplasmic accumulation, and S treatment induced ER-dependent biological effects. Non-invasive imaging in SARS-CoV-2-infected hamsters localized lung pathology with increased ERα lung levels. Postmortem lung experiments from infected hamsters and humans confirmed an increase in cytoplasmic ERα and its colocalization with S in alveolar macrophages. These findings describe the discovery of a S-ERα interaction, imply a role for S as an NRC, and advance knowledge of SARS-CoV-2 biology and coronavirus disease 2019 pathology.

Could Quantum Mechanical Properties Be Reflected on Classical Molecular Dynamics? The Case of Halogenated Organic Compounds of Biological Interest.

Essential to understanding life, the biomolecular phenomena have been an important subject in science, therefore a necessary path to be covered to make progress in human knowledge. To fully comprehend these processes, the non-covalent interactions are the key. In this review, we discuss how specific protein-ligand interactions can be efficiently described by low computational cost methods, such as Molecular Mechanics (MM). We have taken as example the case of the halogen bonds (XB). Albeit generally weaker than the hydrogen bonds (HB), the XBs play a key role to drug design, enhancing the affinity and selectivity toward the biological target. Along with the attraction between two electronegative atoms in XBs explained by the σ-hole model, important orbital interactions, as well as relief of Pauli repulsion take place. Nonetheless, such electronic effects can be only well-described by accurate quantum chemical methods that have strong limitations dealing with supramolecular systems due to their high computational cost. To go beyond the poor description of XBs by MM methods, reparametrizing the force-fields equations can be a way to keep the balance between accuracy and computational cost. Thus, we have shown the steps to be considered when parametrizing force-fields to achieve reliable results of complex non-covalent interactions at MM level for In Silico drug design methods.

Interactions of cantharidin-like inhibitors with human protein phosphatase-5 in a Mg2+ system: molecular dynamics and quantum calculations.

The serine/threonine protein phosphatase type 5 (PP5) is a promising target for designing new antitumor drugs. This enzyme is a member of the PPP phosphatases gene family, which catalyzes a dephosphorylation reaction: a regulatory process in the signal transduction pathway that controls various biological processes. The aim of this work is to study and compare the inhibition of PP5 by ten cantharidin-like inhibitors in order to bring about contributions relevant to the better comprehension of their inhibitory activity. In this theoretical investigation, we used molecular dynamics techniques to understand the role of key interactions that occur in the protein active site; QM calculations were employed to study the interaction mode of these inhibitors in the enzyme. In addition, atoms in molecules (AIM) calculations were carried out to characterize the chemical bonds among the atoms involved and investigate the orbital interactions with their respective energy values. The obtained results suggest that the Arg275, Asn303, His304, His352, Arg400, His427, Glu428, Val429, Tyr451, and Phe446 residues favorably contribute to the interactions between inhibitors and PP5. However, the Asp271 and Asp244 amino acid residues do not favor such interactions for some inhibitors. Through the QM calculations, we can suggest that the reactional energy of the coordination mechanism of these inhibitors in the PP5 active site is quite important and is responsible for the inhibitory activity. The AIM technique employed in this work was essential to get a better comprehension of the transition states acquired from the mechanism simulation. This work offers insights of how cantharidin-like inhibitors interact with human PP5, potentially allowing the design of more specific and even less cytotoxic drugs for cancer treatments. Graphical Abstract Interactions of cantharidin-like inhibitors with human protein phosphatase-5 in a Mg2+ system.

Classical Force Fields Tailored for QM Applications: Is It Really a Feasible Strategy?

Classical molecular dynamics is more and more often coupled to quantum mechanical based techniques as a statistical tool to sample configurations of molecular systems embedded in complex environments. Nonetheless, the classical potentials describing the molecular systems are seldom parametrized to reproduce electronic processes, such as electronic excitations, which are instead very sensitive to the underlining description of the molecular structure. Here, we analyze the challenging case of the peridinin molecule, a natural apocarotenoid responsible for the light-harvesting process in the PCP antenna protein of dinoflagellates. Ground-state structural and vibrational properties, as well as electronic transitions of the pigment are studied by means of quantum-mechanical static and dynamic calculations. Thereafter, classical molecular dynamics simulations are performed with a number of different force-fields, ranging from a popular, general purpose one to refined potentials of increasing level of complexity. From the comparison of classical results with their quantum mechanical counterparts, it appears that, while very poor results are obtained from standard transferrable force-fields, specifically tuned potentials are able to correctly characterize most of the structural and vibrational features of the pigment. Nonetheless, only an advanced parametrization technique is able to give a semiquantitative description of the coupling between vibrations and electronic excitations, thus suggesting that the use of classical MD in combination of QM calculations for the study of photoinduced processes, albeit possible, should be considered with care.

Fine control of chlorophyll-carotenoid interactions defines the functionality of light-harvesting proteins in plants.

Photosynthetic antenna proteins can be thought of as "programmed solvents", which bind pigments at specific mutual orientations, thus tuning the overall energetic landscape and ensuring highly efficient light-harvesting. While positioning of chlorophyll cofactors is well understood and rationalized by the principle of an "energy funnel", the carotenoids still pose many open questions. Particularly, their short excited state lifetime (<25 ps) renders them potential energy sinks able to compete with the reaction centers and drastically undermine light-harvesting efficiency. Exploration of the orientational phase-space revealed that the placement of central carotenoids minimizes their interaction with the nearest chlorophylls in the plant antenna complexes LHCII, CP26, CP29 and LHCI. At the same time we show that this interaction is highly sensitive to structural perturbations, which has a profound effect on the overall lifetime of the complex. This links the protein dynamics to the light-harvesting regulation in plants by the carotenoids.