NLRP3 is an innate immune sensor contributing to the development of different diseases including monogenic autoinflammatory syndromes, gout, atherosclerosis, and Alzheimer’s disease. The molecule sulfonylurea MCC950 is a NLRP3 inflammasome inhibitor with potential clinical utility. However, the mechanism of action of MCC950 remains unknown. Here, we characterize the mechanism of action of MCC950 in both wild-type and autoinflammatory-related NLRP3 mutants, demonstrating that MCC950 closes the ‘open’ conformation of active NLRP3.

The solvent polarity parameter E T (30) is newly measured from the solvatochromism of the betaine dye 30 for 84 solvents and re-measured for 186 additional ones. The results are organized in a database. It is shown that the validity of linear solvation energy relationships used for the determination of secondary E T (30) values is limited to non-hydrogen-bond donor solvents. Relationships with the chain length n are given for the determination of tertiary E T (30) values of the homologous H(CH 2 ) n Y solvent series. The parameter E T (30) is orthogonal to the function of the refractive index (n 2 À 1) / (2n 2 + 1). For non hydrogen-bond donor solvents, this allows to enter E T (30) as an almost pure electrostatic parameter in a new linear solvation energy relationship.

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Although engineered by millions of years of evolution, the cellular machinery is not flawless, and errors regularly appear during DNA replication. The subsequent alteration of the stored genetic message results in a mutation and might be the starting point of important health disorders. The question therefore is what causes DNA mutations? All living organisms are constantly exposed to a number of external agents such as free radicals and to radiation, which may lead to induced mutations. There are also mutations happening without invoking the action of any exogenous element, the so-called spontaneous mutations. The former can be partially controlled by avoiding exposure to high-risk environments, while the latter are more intriguing because their origin is unclear and difficult to determine. As noted by Watson and Crick when they first discovered the DNA structure, the correct replication of DNA rests on the assumption that the base pairs remain in their most stable, canonical form. However, protons along the interbase hydrogen-bond network are not static entities. They can in fact interchange their positions in DNA bases through proton transfer (PT) reactions before strands unwind, giving rise to noncanonical structures defined as rare tautomers. The importance of these rare tautomers was also cleverly anticipated by Watson and Crick and some years later claimed by Löwdin to be a source of spontaneous mutations. In Watson and Crick's words: "It would be of interest to know the precise difference in free energy between the various tautomeric forms under physiological conditions." Unfortunately, rare tautomeric forms are very difficult to detect, so no direct and accurate free energy measure has been discerned. In contrast, theoretical chemistry is making good progress toward the quantification of PT reactions in DNA and their biological consequences. This Account touches upon the theoretical studies devoted to appraising the importance of rare tautomers as promoters of spontaneous mutations. We focus in particular on the crucial role played by the biological environment on DNA stability. It has now been demonstrated that valuable macroscopic predictions require not only highly accurate theories but also refined chemical models. Hybrid quantum mechanics/molecular mechanics (QM/MM) simulations performed on short but complete DNA sequence fragments emerge in this context as the most adequate tools. In addition, these methods can be used to quantify the effect of different external agents on the PT tautomeric equilibria and, eventually, to conveniently handle them. This is the case for the possible alteration of the naturally observed mutation rate by exposure to intense electric fields. Theoretical predictions envision in this respect promising applications of ultrashort electric pulses in medicine to selectively modify the mutated/canonical ratio in DNA.

Accurate calculations of the double proton transfer (DPT) in the adenine-thymine base pair (AT) were presented in a previous work [J. Phys. Chem. A 2009, 113, 7892.] where we demonstrated that the mechanism of the reaction in solution is strongly affected by surrounding water. Here we extend our methodology to the guanine-cytosine base pair (GC), for which it turns out that the proton transfer in the gas phase is a synchronous concerted mechanism. The O(G)-H-N(C) hydrogen bond strength emerges as the key parameter in this process, to the extent that complete transfer takes place by means of this hydrogen bond. Since the main effect of the molecular environment is precisely to weaken this bond, the direct proton transfer is not possible in solution, and thus the tautomeric equilibrium must be assisted by surrounding water molecules in an asynchronous concerted mechanism. This result demonstrates that water plays a crucial role in proton reactions. It does not act as a passive element but actually catalyzes the DPT.

We report the first density functional study of water catalytic effect in the double proton transfer (DPT) taking place in the adenine-thymine (AT) base pair. To gain more insight regarding the accuracy of several theoretical methods, the ability of various functionals and models for describing the geometry of this system has first been checked. According to our results, BP86/6-311++G(d,p) is the best option for describing the solvation effects in AT when applied to a two-water-molecule-featuring model. The two possible mechanisms for DPT in solution are explored: in the first one, water molecules only remain passive elements, whereas in the second one they are directly included in the reaction path. For the noncatalyzed mechanism, the stable structures constitute the canonical form of the base pair and the first proton transfer product. Nevertheless, by involving the two water molecules in the reaction, we found three stable species: canonical base pair, first proton transfer product, and double proton transfer product. Although the thermodynamic analysis confirms that AT does not contribute to spontaneous mutation through proton transfer catalyzed by surrounding water, our results suggest that microhydration may play a crucial role for DPT reaction in others DNA or RNA basis pair.

Empirical parameters of solvents describing their hydrogen-bond (HB) acidity (e.g., the Kamlet-Taft α parameter) are often difficult to determine for new solvents because they are not directly related to a single definition process. Here, we propose a simple method based on one probe, the betaine dye 30, and one reference process, the solvatochromism of this dye, measured by its first electronic transition energy, ET(30). These ET(30) values are calculated within the time-dependent density functional theory framework, using a polarizable continuum solvent model (PCM). The part of ET(30) values that is not included in the PCM calculation is taken as the HB component of the measured ET(30) values, allowing us to deduce a solvent HB acidity parameter α1. The validity of this simple model is assessed by good linear correlations between α1 and a variety of solute properties mainly depending on the solvent's HB acidity. The quality of fit observed with α1 is at least comparable with that obtained by previous solvent HB acidity scales. The simplicity of our method is illustrated by the determination of α1 and of its companion, the electrostatic solvent parameter ES, for some new green solvents derived from glycerol.

In DNA, base pairs are involved in two reciprocal interactions: interbase hydrogen bonds and stacking. Furthermore, base pairs also undergo the effects of the external entities present in the biological environment, such as water molecules and cations. In this contribution, the double spontaneous mutation has been studied with hybrid theoretical tools in a DNA-embedded guanine-cytosine model accounting for the impact of the first hydration shell. According to our findings, the combination of the neighboring base pairs and surrounding water molecules plays a crucial role in the double proton transfer. Indeed, as a consequence of these interactions, the double proton transfer (DPT) mechanism is altered: on the one hand, stacking and hydration strongly affect the geometry of base pairs, and, on the other hand, vicinal water molecules may play an active role in the tautomeric equilibrium by catalyzing the proton transfer reaction.