The extended charge equilibration (EQeq) scheme computes atomic partial charges using the experimentally measured ionization potentials and electron affinities of atoms. However, EQeq erroneously predicts constant (environment independent) charges for high-oxidation-state transition metals in amine-templated metal oxide (ATMO) compounds, contrary to the variation observed in iterative Hirshfeld (Hirshfeld-I) charges, bond-valence sum calculations, and formal oxidation state calculations. To fix this problem, we present a simple, noniterative empirical pairwise correction based on the Pauling bond-order/distance relationship, which we denote EQeq+C. We parametrized the corrections to reproduce the Hirshfeld-I charges of ATMO compounds and REPEAT charges of metal organic framework (MOF) compounds. The EQeq+C correction fixes the metal charge problem and significantly improves the partial atomic charges compared to EQeq. We demonstrate the transferability of the parametrization by applying it to a set of unrelated dipeptides. After an initial parametrization, the EQeq+C correction requires minimal computational overhead, making it suitable for treating large unit cell solids and performing large-scale computational materials screening.
An atomistic understanding of metal transport in the human body is critical to anticipate the side effects of metal-based therapeutics and holds promise for new drugs and drug delivery designs in itself. Human serum transferrin (hTF) is a central part of the transport processes with its ubiquitous ferrying of physiological Fe(III) and other transition metals, including to tightly controlled parts of the body. There is an atomistic mechanism for the uptake process with Fe(III), but not for the release process or for other metals. This study provides initial insight into these processes for a range of transition metals (Ti(IV), Co(III), Fe(III), Ga(III), Cr(III), Fe(II), Zn(II)) through fully atomistic, extensive QM/DMD sampling and a new technique we developed to calculate relative binding affinities between metal cations and the protein. It identifies protonation of Tyr188 as a trigger for metal release, rather than protonation of Lys206 or Lys296. The study identifies difficulty of metal release from hTF as potentially related to cytotoxicity. Simulations identify a few critical interactions that stabilize the metal-binding site in a flexible, nuanced manner. Statement of SignificanceHuman serum transferrin (hTF) is a Fe(III) transport protein that may be implicated in the cytotoxicity of non-native metals like Ti(IV), Ga(III), and Al(III). However, hTF transport and especially release are not well studied for metals beyond Fe(III). In this study we computationally investigate the uptake and release mechanisms and affinities for a range of transition metals (Ti(IV), Co(III), Fe(III), Ga(III), Cr(III), Fe(II), Zn(II)). We find that the tightest binding metals of this list are Ti(IV) and Ga(III): the potentially cytotoxic ones.
Azacyclo- and azabicycloalkanone peptidomimetics were synthesized regio- and diastereoselectively by iodoacetoxylation and transannular amidation reactions on unsaturated lactam precursors contingent on ring size, olefin position, solvent, and hypervalent iodine(III) reagent. 4-Iodopyrrolizidinone 1, 7-iodoindolizidinone 2, and 4-iodo-5-acetoxylactams (e.g., 6 and 7) were made stereospecifically from 7-9-membered olefins 16, iodine, and hypervalent iodine(III) in acetonitrile or toluene, respectively. X-ray crystallography demonstrated potential for mimicry of natural peptide turn side chain and backbone conformations.
New Delhi Metallo-β-lactamase (NDM) grants resistance to a broad spectrum of β-lactam antibiotics including last-resort carbapenems and is emerging as a global antibiotic resistance threat. Limited zinc availability adversely impacts the ability of NDM-1 to provide resistance, but a number of clinical variants have emerged that are more resistant to zinc scarcity (e.g., NDM-15). To provide a novel tool to better study metal ion sequestration in host-pathogen interactions, we describe the development of a fluorescent probe that reports on the dynamic metallation state of NDM within E. coli. The thiol-containing probe selectively coordinates the dizinc metal cluster of NDM and results in a 17-fold increase in fluorescence intensity. Reversible binding enables competition and time-dependent studies that reveal fluorescence changes used to detect enzyme localization, substrate and inhibitor engagement, and changes to metallation state through the imaging of live E. coli using confocal microscopy. NDM-1 is shown to be susceptible to demetallation by intracellular and extracellular metal chelators in a live-cell model of zinc dyshomeostasis, whereas the NDM-15 metallation state is shown to be more resistant to zinc flux. The development of this reversible turn-on fluorescent probe for the metallation state of NDM provides a new tool for monitoring the impact of metal ion sequestration by host defense mechanisms and to detect inhibitor target engagement during the development of therapeutics to counter this resistance determinant.
The pH dependence of enzyme fold stability and catalytic activity is a fundamentally dynamic, structural property which is difficult to study. Computational methods, particularly constant pH molecular dynamics (CpHMD), are the best situated tools for this. However, these often struggle with affordable sampling of sufficiently long timescales, accuracy of pKa prediction, and verification of the structures they generate. We introduce Titr-DMD, an affordable CpHMD method with a protonation state sampler that can be systematically improved, to circumvent these issues. We benchmark the method on a set of proteins with experimentally attested pKa and on the pH triggered conformational change in a staphylococcal nuclease mutant, a rare experimental study of such behavior. Our results show Titr-DMD to be an effective method to study pH coupled protein dynamics. File list (2) download file view on ChemRxiv Supplementary Information.pdf (607.83 KiB) download file view on ChemRxiv Main Text.pdf (1.87 MiB)
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