Water in Protic Ionic Liquid Electrolytes: From Solvent Separated Ion Pairs to Water Clusters

Abstract The large electrochemical and cycling stability of “water‐in‐salt” systems have rendered promising prospective electrolytes for batteries. The impact of addition of water on the properties of ionic liquids has already been addressed in several publications. In this contribution, we focus on the changes in the state of water. Therefore, we investigated the protic ionic liquid N ‐butyl‐pyrrolidinium bis(trifluoromethanesulfonyl)imide with varying water content at different temperatures with the aid of molecular dynamics simulations. It is revealed that at very low concentrations, the water is well dispersed and best characterized as shared solvent molecules. At higher concentrations, the water forms larger aggregates and is increasingly approaching a bulk‐like state. While the librational and rotational dynamics of the water molecules become faster with increasing concentration, the translational dynamics are found to become slower. Further, all dynamics are found to be faster if the temperature increases. The trends of these findings are well in line with the experimental measured conductivities.From single molecules to bulk liquid : The state of water in a protic ionic liquid at different concentration is investigated by the aid of molecular dynamics simulations. At a low concentration, the water shows the behavior of free molecules. With increasing concentration, the formation of clusters can be observed. Finally, at concentrations near the phase separation the behavior approaches that of the bulk liquid. imag

Mechanism-Based Redesign of GAP to Activate Oncogenic Ras

Ras GTPases play a crucial role in cell signaling pathways. Mutations of the Ras gene occur in about one third of cancerous cell lines and are often associated with detrimental clinical prognosis. Hot spot residues Gly12, Gly13, and Gln61 cover 97% of oncogenic mutations, which impair the enzymatic activity in Ras. Using QM/MM free energy calculations, we present a two-step mechanism for the GTP hydrolysis catalyzed by the wild-type Ras.GAP complex. We found that the deprotonation of the catalytic water takes place via the Gln61 as a transient Brønsted base. We also determined the reaction profiles for key oncogenic Ras mutants G12D and G12C using QM/MM minimizations, matching the experimentally observed loss of catalytic activity, thereby validating our reaction mechanism. Using the optimized reaction paths, we devised a fast and accurate procedure to design GAP mutants that activate G12D Ras. We replaced GAP residues near the active site and determined the activation barrier for 190 single mutants. We furthermore built a machine learning for ultrafast screening, by fast prediction of the barrier heights, tested both on the single and double mutations. This work demonstrates that fast and accurate screening can be accomplished via QM/MM reaction path optimizations to design protein sequences with increased catalytic activity. Several GAP mutations are predicted to re-enable catalysis in oncogenic G12D, offering a promising avenue to overcome aberrant Ras-driven signal transduction by activating enzymatic activity instead of inhibition. The outlined computational screening protocol is readily applicable for designing ligands and cofactors analogously

Investigating the Unbinding of Muscarinic Antagonists from the Muscarinic 3 Receptor

Patient symptom relief is often heavily influenced by the residence time of the inhibitor-target complex. For the human muscarinic receptor 3 (hMR3), tiotropium is a long-acting bronchodilator used in conditions such as asthma or chronic obstructive pulmonary disease (COPD). The mechanistic insights into this inhibitor remain unclear; specifically, the elucidation of the main factors determining the unbinding rates could help develop the next generation of antimuscarinic agents. Using our novel unbinding algorithm, we were able to investigate ligand dissociation from hMR3. The unbinding paths of tiotropium and two of its analogues, N-methylscopolamin and homatropine methylbromide, show a consistent qualitative mechanism and allow us to identify the structural bottleneck of the process. Furthermore, our machine learning-based analysis identified key roles of the ECL2/TM5 junction involved in the transition state. Additionally, our results point to relevant changes at the intracellular end of the TM6 helix leading to the ICL3 kinase domain, highlighting the closest residue L482. This residue is located right between two main protein binding sites involved in signal transduction for hMR3's activation and regulation. We also highlight key pharmacophores of tiotropium that play determining roles in the unbinding kinetics and could aid toward drug design and lead optimization

Investigating the Unbinding of Muscarinic Antagonists from the Muscarinic 3 Receptor

Patient symptom relief is often heavily influenced by the residence time of the inhibitor–target complex. For the human muscarinic receptor 3 (hMR3), tiotropium is a long-acting bronchodilator used in conditions such as asthma or chronic obstructive pulmonary disease (COPD). The mechanistic insights into this inhibitor remain unclear; specifically, the elucidation of the main factors determining the unbinding rates could help develop the next generation of antimuscarinic agents. Using our novel unbinding algorithm, we were able to investigate ligand dissociation from hMR3. The unbinding paths of tiotropium and two of its analogues, N-methylscopolamin and homatropine methylbromide, show a consistent qualitative mechanism and allow us to identify the structural bottleneck of the process. Furthermore, our machine learning-based analysis identified key roles of the ECL2/TM5 junction involved in the transition state. Additionally, our results point to relevant changes at the intracellular end of the TM6 helix leading to the ICL3 kinase domain, highlighting the closest residue L482. This residue is located right between two main protein binding sites involved in signal transduction for hMR3′s activation and regulation. We also highlight key pharmacophores of tiotropium that play determining roles in the unbinding kinetics and could aid toward drug design and lead optimization

One-to-many-relations in morphology, syntax, and semantics

The standard view of the form-meaning interfaces, as embraced by the great majority of contemporary grammatical frameworks, consists in the assumption that meaning can be associated with grammatical form in a one-to-one correspondence. Under this view, composition is quite straightforward, involving concatenation of form, paired with functional application in meaning. In this book, we discuss linguistic phenomena across several grammatical sub-modules (morphology, syntax, semantics) that apparently pose a problem to the standard view, mapping out the potential for deviation from the ideal of one-to-one correspondences, and develop formal accounts of the range of phenomena. We argue that a constraint-based perspective is particularly apt to accommodate deviations from one-to-many correspondences, as it allows us to impose constraints on full structures (such as a complete word or the interpretation of a full sentence) instead of deriving such structures step by step. Most of the papers in this volume are formulated in a particular constraint-based grammar framework, Head-driven Phrase Structure Grammar. The contributions investigate how the lexical and constructional aspects of this theory can be combined to provide an answer to this question across different linguistic sub-theories

One-to-many-relations in morphology, syntax, and semantics

The standard view of the form-meaning interfaces, as embraced by the great majority of contemporary grammatical frameworks, consists in the assumption that meaning can be associated with grammatical form in a one-to-one correspondence. Under this view, composition is quite straightforward, involving concatenation of form, paired with functional application in meaning. In this book, we discuss linguistic phenomena across several grammatical sub-modules (morphology, syntax, semantics) that apparently pose a problem to the standard view, mapping out the potential for deviation from the ideal of one-to-one correspondences, and develop formal accounts of the range of phenomena. We argue that a constraint-based perspective is particularly apt to accommodate deviations from one-to-many correspondences, as it allows us to impose constraints on full structures (such as a complete word or the interpretation of a full sentence) instead of deriving such structures step by step. Most of the papers in this volume are formulated in a particular constraint-based grammar framework, Head-driven Phrase Structure Grammar. The contributions investigate how the lexical and constructional aspects of this theory can be combined to provide an answer to this question across different linguistic sub-theories

One-to-many-relations in morphology, syntax, and semantics

The standard view of the form-meaning interfaces, as embraced by the great majority of contemporary grammatical frameworks, consists in the assumption that meaning can be associated with grammatical form in a one-to-one correspondence. Under this view, composition is quite straightforward, involving concatenation of form, paired with functional application in meaning. In this book, we discuss linguistic phenomena across several grammatical sub-modules (morphology, syntax, semantics) that apparently pose a problem to the standard view, mapping out the potential for deviation from the ideal of one-to-one correspondences, and develop formal accounts of the range of phenomena. We argue that a constraint-based perspective is particularly apt to accommodate deviations from one-to-many correspondences, as it allows us to impose constraints on full structures (such as a complete word or the interpretation of a full sentence) instead of deriving such structures step by step. Most of the papers in this volume are formulated in a particular constraint-based grammar framework, Head-driven Phrase Structure Grammar. The contributions investigate how the lexical and constructional aspects of this theory can be combined to provide an answer to this question across different linguistic sub-theories

One-to-many-relations in morphology, syntax, and semantics

The standard view of the form-meaning interfaces, as embraced by the great majority of contemporary grammatical frameworks, consists in the assumption that meaning can be associated with grammatical form in a one-to-one correspondence. Under this view, composition is quite straightforward, involving concatenation of form, paired with functional application in meaning. In this book, we discuss linguistic phenomena across several grammatical sub-modules (morphology, syntax, semantics) that apparently pose a problem to the standard view, mapping out the potential for deviation from the ideal of one-to-one correspondences, and develop formal accounts of the range of phenomena. We argue that a constraint-based perspective is particularly apt to accommodate deviations from one-to-many correspondences, as it allows us to impose constraints on full structures (such as a complete word or the interpretation of a full sentence) instead of deriving such structures step by step. Most of the papers in this volume are formulated in a particular constraint-based grammar framework, Head-driven Phrase Structure Grammar. The contributions investigate how the lexical and constructional aspects of this theory can be combined to provide an answer to this question across different linguistic sub-theories

One-to-many-relations in morphology, syntax, and semantics

The standard view of the form-meaning interfaces, as embraced by the great majority of contemporary grammatical frameworks, consists in the assumption that meaning can be associated with grammatical form in a one-to-one correspondence. Under this view, composition is quite straightforward, involving concatenation of form, paired with functional application in meaning. In this book, we discuss linguistic phenomena across several grammatical sub-modules (morphology, syntax, semantics) that apparently pose a problem to the standard view, mapping out the potential for deviation from the ideal of one-to-one correspondences, and develop formal accounts of the range of phenomena. We argue that a constraint-based perspective is particularly apt to accommodate deviations from one-to-many correspondences, as it allows us to impose constraints on full structures (such as a complete word or the interpretation of a full sentence) instead of deriving such structures step by step. Most of the papers in this volume are formulated in a particular constraint-based grammar framework, Head-driven Phrase Structure Grammar. The contributions investigate how the lexical and constructional aspects of this theory can be combined to provide an answer to this question across different linguistic sub-theories

One-to-many-relations in morphology, syntax, and semantics

The standard view of the form-meaning interfaces, as embraced by the great majority of contemporary grammatical frameworks, consists in the assumption that meaning can be associated with grammatical form in a one-to-one correspondence. Under this view, composition is quite straightforward, involving concatenation of form, paired with functional application in meaning. In this book, we discuss linguistic phenomena across several grammatical sub-modules (morphology, syntax, semantics) that apparently pose a problem to the standard view, mapping out the potential for deviation from the ideal of one-to-one correspondences, and develop formal accounts of the range of phenomena. We argue that a constraint-based perspective is particularly apt to accommodate deviations from one-to-many correspondences, as it allows us to impose constraints on full structures (such as a complete word or the interpretation of a full sentence) instead of deriving such structures step by step. Most of the papers in this volume are formulated in a particular constraint-based grammar framework, Head-driven Phrase Structure Grammar. The contributions investigate how the lexical and constructional aspects of this theory can be combined to provide an answer to this question across different linguistic sub-theories