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A quantitative metric for organic radical stability and persistence using thermodynamic and kinetic features† † Electronic supplementary information (ESI) available: 9 supplemental figures and 3 supplemental tables. See DOI: 10.1039/d1sc02770k

ABSTRACT: Long-lived organic radicals are promising candidates for the development of high-performance energy solutions such as organic redox batteries, transistors, and light-emitting diodes. However, “stable” organic radicals that remain unreactive for an extended time and that can be stored and handled under ambient conditions are rare. A necessary but not sufficient condition for organic radical stability is the presence of thermodynamic stabilization, such as conjugation with an adjacent π-bond or lone-pair, or hyperconjugation with a σ-bond. However, thermodynamic factors alone do not result in radicals with extended lifetimes: many resonance-stabilized radicals are transient species that exist for less than a millisecond. Kinetic stabilization is also necessary for persistence, such as steric effects that inhibit radical dimerization or reaction with solvent molecules. We describe a quantitative approach to map organic radical stability, using molecular descriptors intended to capture thermodynamic and kinetic considerations. The comparison of an extensive dataset of quantum chemical calculations of organic radicals with experimentally-known stable radical species reveals a region of this feature space where long-lived radicals are located. These descriptors, based upon maximum spin density and buried volume, are combined into a single metric, the radical stability score, that outperforms thermodynamic scales based on bond dissociation enthalpies in identifying remarkably long-lived radicals. This provides an objective and accessible metric for use in future molecular design and optimization campaigns. We demonstrate this approach in identifying Pareto-optimal candidates for stable organic radicals. Molecular descriptors encoding kinetic and thermodynamic stabilization capture the difference between transient and persistent organic radicals.

SUBMITTER: Sowndarya S. V. S

PROVIDER: S-EPMC8514092 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundMolecular phenomena driving pathological aggregation in neurodegenerative diseases are not completely understood yet. Peculiar is the case of Spinocerebellar Ataxia 3 (SCA3) where the conformational properties of the AT-3 N-terminal region, also called Josephin Domain (JD), play a key role in the first step of aggregation, having the JD an amyloidogenic propensity itself. For this reason, unraveling the intimate relationship between JD structural features and aggregation tendency may lead to a step forward in understanding the pathology and rationally design a cure. In this connection, computational modeling has demonstrated to be helpful in exploring the protein molecular dynamics and mechanism of action.ResultsConformational dynamics of the JD is here finely investigated by replica exchange molecular dynamics simulations able to sample the microsecond time scale and to provide both a thermodynamic and kinetic description of the protein conformational changes. Accessible structural conformations of the JD have been identified in: open, intermediate and closed like arrangement. Data indicated the closed JD arrangement as the most likely protein arrangement. The protein transition from closed toward intermediate/open states was characterized by a rate constant higher than 700 ns. This result also explains the inability of classical molecular dynamics to explore transitions from closed to open JD configuration on a time scale of hundreds of nanoseconds.ConclusionThis work provides the first kinetic estimation of the JD transition pathway from open-like to closed-like arrangement and vice-versa, indicating the closed-like arrangement as the most likely configuration for a JD in water environment. More widely, the importance of our results is also underscored considering that the ability to provide a kinetic description of the protein conformational changes is a scientific challenge for both experimental and theoretical approaches to date.ReviewersThis article was reviewed by Oliviero Carugo, Bojan Zagrovic.

Dataset Information

A quantitative metric for organic radical stability and persistence using thermodynamic and kinetic features† † Electronic supplementary information (ESI) available: 9 supplemental figures and 3 supplemental tables. See DOI: 10.1039/d1sc02770k

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