Probing the environmental sensitivity of thymine CO vibrations through infrared spectra simulations.

Infrared spectroscopy is widely used to probe the structural organization of biologically relevant molecules, including peptides, proteins, and nucleic acids. The latter show significant structural diversity, and specific infrared bands provide insights into their conformational ensembles. Among DNA/RNA infrared bands, the CO stretching modes are especially useful, as they are sensitive to the distinct structural arrangements within nucleic acids.

Size-dependent effect of nano-confinement of water in an ionic liquid matrix at low temperature.

One of the leading hypotheses explaining water's anomalies is a metastable liquid-liquid phase transition (LLPT) at high pressure and low temperatures, which remains experimentally elusive due to homogeneous nucleation. Infrared spectroscopy experiments have shown that adding hydrazinium trifluoroacetate to water induces a sharp, reversible LLPT at ambient pressure, potentially originating from the same underlying mechanism as in pure water. In a previous work, we demonstrated that this transition can be attributed to the behavior of pure water only when nanosegregation of the aqueous component is brought into play.

Conformational heterogeneity and protonation equilibria shape the photocycle branching in channelrhodopsin-2.

Channelrhodopsin-2 is a photoactive membrane protein serving as an ion channel, gathering significant interest for its applications in optogenetics. Despite extensive investigation, several aspects of its photocycle remain elusive and continue to be subjects of ongoing debate. Of particular interest are the localization of the P480 intermediate within the photocycle and the timing of the deprotonation of glutamic acid E90, a critical residue for ChR2 functioning.

Early prediction of spinodal-like relaxation events in supercooled liquid water.

Several computational studies on different water models reported evidence of a phase transition in supercooled conditions between two liquid states of water differing in density: the high-density liquid (HDL) and the low-density liquid (LDL). Yet, conclusive experimental evidence of the existence of a phase transition between the two liquid water phases could not be obtained due to fast crystallization in the region where the phase transition should occur. For the same reason, the investigation of possible transition mechanisms between the two phases is committed to computational investigations.

Tuning the low-temperature phase behavior of aqueous ionic liquids.

Water's anomalous behavior is often explained using a two-liquid model, where two types of water, high-density liquid (HDL) and low-density liquid (LDL), can be separated a liquid-liquid phase transition (LLPT) at low temperature. Mixtures of water and the ionic liquid hydrazinium trifluoroacetate were suggested to also show an LLPT but with the advantage that there is no rapid ice crystallization hampering its observation. It remains controversial whether these solutions exhibit an LLPT or are instead associated with complex phase separation phenomena.

A statistical mechanical model of supercooled water based on minimal clusters of correlated molecules.

In this paper, we apply a theoretical model for fluid state thermodynamics to investigate simulated water in supercooled conditions. This model, which we recently proposed and applied to sub- and super-critical fluid water [Zanetti-Polzi et al., J.

Mechanism and Dynamics of Photodecarboxylation Catalyzed by Lactate Monooxygenase.

Photoenzymes are a rare class of biocatalysts that use light to facilitate chemical reactions. Many of these catalysts utilize a flavin cofactor to absorb light, suggesting that other flavoproteins might have latent photochemical functions. Lactate monooxygenase is a flavin-dependent oxidoreductase previously reported to mediate the photodecarboxylation of carboxylates to afford alkylated flavin adducts.

Thermodynamic Evolution of a Metamorphic Protein: A Theoretical-Computational Study of Human Lymphotactin.

Metamorphic, or fold-switching, proteins feature different folds that are physiologically relevant. The human chemokine XCL1 (or Lymphotactin) is a metamorphic protein that features two native states, an [Formula: see text] and an all[Formula: see text] fold, which have similar stability at physiological condition. Here, extended molecular dynamics (MD) simulations, principal component analysis of atomic fluctuations and thermodynamic modeling based on both the configurational volume and free energy landscape, are used to obtain a detailed characterization of the conformational thermodynamics of human Lymphotactin and of one of its ancestors (as was previously obtained by genetic reconstruction).

Evidence for a high pK of an aspartic acid residue in the active site of CALB by a fully atomistic multiscale approach.

Lipase B (CALB) is a paradigm for the family of lipases. At pH 7, the optimal pH for catalysis, the protonation state of an aspartic acid of the active site (Asp134) could not be conclusively assigned. In fact, the pK estimate provided by a widely used computational tool, namely PropKa, that predicts pK values of ionizable groups in proteins based on the crystallographic structure, is only slightly above 7 (pK = 7.

Photophysical and Computational Insights into Ag(I) Complexation of Porphyrinic Covalent Cages Equipped with Triazoles-Incorporating Linkers.

The photophysical characterization of four supramolecular complexes based on covalent cages , , , and , consisting in either two free-base porphyrins or one Zn(II) porphyrin and one free-base porphyrin connected by four flexible linkers of different lengths incorporating triazole binding sites, and their Ag(I) complexation are reported. The complexation processes have been followed by means of absorption and emission spectroscopies, and a comprehensive computational study explains the behavior of the free-base porphyrin-containing cages. Absorption and emission features have been interpreted on the bases of conformational changes, metalation processes, and modification of energy transfer efficiencies occurring in the different cases.

A general statistical mechanical model for fluid system thermodynamics: Application to sub- and super-critical water.

We propose in this paper a theoretical model for fluid state thermodynamics based on modeling the fluctuation distributions and, hence, the corresponding moment generating functions providing the free energy of the system. Using the relatively simple and physically coherent gamma model for the fluctuation distributions, we obtain a complete theoretical equation of state, also giving insight into the statistical/molecular organization and phase or pseudo-phase transitions occurring under the sub- and super-critical conditions, respectively. Application to sub- and super-critical fluid water and a comparison with the experimental data show that this model provides an accurate description of fluid water thermodynamics, except close to the critical point region where limited but significant deviations from the experimental data occur.

Segregation on the nanoscale coupled to liquid water polyamorphism in supercooled aqueous ionic-liquid solution.

The most intriguing hypothesis explaining many water anomalies is a metastable liquid-liquid phase transition (LLPT) at high pressure and low temperatures, experimentally hidden by homogeneous nucleation. Recent infrared spectroscopic experiments showed that upon addition of hydrazinium trifluoroacetate to water, the supercooled ionic solution undergoes a sharp, reversible LLPT at ambient pressure, possible offspring of that in pure water. Here, we calculate the temperature-dependent signature of the OH-stretching band, reporting on the low/high density phase of water, in neat water and in the same experimentally investigated ionic solution.

Tuning Proton Transfer Thermodynamics in SARS-CoV-2 Main Protease: Implications for Catalysis and Inhibitor Design.

The catalytic reaction in SARS-CoV-2 main protease is activated by a proton transfer (PT) from Cys145 to His41. The same PT is likely also required for the covalent binding of some inhibitors. Here we use a multiscale computational approach to investigate the PT thermodynamics in the apo enzyme and in complex with two potent inhibitors, N3 and the α-ketoamide .

A computational insight into the relationship between side chain IR line shapes and local environment in fibril-like structures.

Infrared spectroscopy is a widely used technique to characterize protein structures and protein mediated processes. While the amide I band provides information on proteins' secondary structure, amino acid side chains are used as infrared probes for the investigation of protein reactions and local properties. In this paper, we use a hybrid quantum mechanical/classical molecular dynamical approach based on the perturbed matrix method to compute the infrared band due to the C=O stretching mode of amide-containing side chains.

Inhibitor binding influences the protonation states of histidines in SARS-CoV-2 main protease.

The main protease (M) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is an attractive target for antiviral therapeutics. Recently, many high-resolution apo and inhibitor-bound structures of M, a cysteine protease, have been determined, facilitating structure-based drug design. M plays a central role in the viral life cycle by catalyzing the cleavage of SARS-CoV-2 polyproteins.

Tuning Proton Transfer Thermodynamics in SARS-Cov-2 Main Protease: Implications for Catalysis and Inhibitor Design.

In this comutational work a hybrid quantum mechanics/molecular mechanics approach, the MD-PMM approach, is used to investigate the proton transfer reaction the activates the catalytic activity of SARS-CoV-2 main protease. The proton transfer thermodynamics is investigated for the apo ensyme (i.e.

Inhibitor binding influences the protonation states of histidines in SARS-CoV-2 main protease.

The main protease (M ) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is an attractive target for antiviral therapeutics. Recently, many high-resolution apo and inhibitor-bound structures of M , a cysteine protease, have been determined, facilitating structure-based drug design. M plays a central role in the viral life cycle by catalyzing the cleavage of SARS-CoV-2 polyproteins.

Cooperative protein-solvent tuning of proton transfer energetics: carbonic anhydrase as a case study.

We investigate the coupling between the proton transfer (PT) energetics and the protein-solvent dynamics using the intra-molecular PT in wild type (wt) human carbonic anhydrase II and its ten-fold faster mutant Y7F/N67Q as a test case. We calculate the energy variation upon PT, and from that we also calculate the PT reaction free energy, making use of a hybrid quantum mechanics/molecular dynamics approach. In agreement with the experimental data, we obtain that the reaction free energy is basically the same in the two systems.

Allosteric Control of Naphthalene Diimide Encapsulation and Electron Transfer in Porphyrin Containers: Photophysical Studies and Molecular Dynamics Simulation.

The complexation processes of N,N'-dibutyl-1,4,5,8-naphthalene diimide (NDI) into two types of π-electron-rich molecular containers consisting of two Zn(II)-porphyrins connected by four flexible linkers of two different lengths, were characterized by means of absorption and emission spectroscopies and molecular dynamics simulation. Notably, the addition of NDI leads to a strong quenching of the fluorescence of both cages only when they are in an open conformation suitable for guest encapsulation, a situation triggered by silver(I) ions binding to the lateral triazoles. Molecular dynamics simulations confirm the fast binding of NDI, likely assisted by NDI-silver(I) interactions.

Fully Atomistic Multiscale Approach for p Prediction.

The ionization state of titratable amino acids strongly affects proteins structure and functioning in a large number of biological processes. It is therefore essential to be able to characterize the p of ionizable groups inside proteins and to understand its microscopic determinants in order to gain insights into many functional properties of proteins. A big effort has been devoted to the development of theoretical approaches for the prediction of deprotonation free energies, yet the accurate theoretical/computational calculation of p values is recognized as a current challenge.

Modeling amino-acid side chain infrared spectra: the case of carboxylic residues.

Infrared (IR) spectroscopy is commonly utilized for the investigation of protein structures and protein-mediated processes. While the amide I band provides information on protein secondary structures, amino acid side chains are used as IR probes for the investigation of protein reactions, such as proton pumping in rhodopsins. In this work, we calculate the IR spectra of the solvated aspartic acid, with both zwitterionic and protonated backbones, and of a capped form, i.

The Interaction between Amyloid Prefibrillar Oligomers of Salmon Calcitonin and a Lipid-Raft Model: Molecular Mechanisms Leading to Membrane Damage, Ca-Influx and Neurotoxicity.

To investigate the interaction between amyloid assemblies and "lipid-rafts", we performed functional and structural experiments on salmon calcitonin (sCT) solutions rich in prefibrillar oligomers, proto- and mature-fibers interacting with liposomes made of monosialoganglioside-GM1 (4%), DPPC (48%) and cholesterol (48%). To focus on the role played by electrostatic forces and considering that sCT is positive and GM1 is negative at physiologic pH, we compared results with those relative to GM1-free liposomes while, to assess membrane fluidity effects, with those relative to cholesterol-free liposomes. We investigated functional effects by evaluating Ca-influx in liposomes and viability of HT22-DIFF neurons.

Hydration Shell of Antifreeze Proteins: Unveiling the Role of Non-Ice-Binding Surfaces.

Antifreeze proteins (AFPs) have the ability to inhibit ice growth by binding to ice nuclei. Their ice-binding mechanism is still unclear, yet the hydration layer is thought to play a fundamental role. Here, we use molecular dynamics simulations to characterize the hydration shell of two AFPs and two non-AFPs.

Tip-Enhanced Infrared Difference-Nanospectroscopy of the Proton Pump Activity of Bacteriorhodopsin in Single Purple Membrane Patches.

Photosensitive proteins embedded in the cell membrane (about 5 nm thickness) act as photoactivated proton pumps, ion gates, enzymes, or more generally, as initiators of stimuli for the cell activity. They are composed of a protein backbone and a covalently bound cofactor (e.g.