Molecular-scale description of interfacial mass transfer in phase-separated aqueous secondary organic aerosol

Liquid–liquid phase-separated (LLPS) aerosol particles are known to exhibit increased cloud condensation nuclei (CCN) activity compared to well-mixed ones due to a complex effect of low surface tension and non-ideal mixing. The relation between the two contributions as well as the molecular-scale mechanism of water uptake in the presence of an internal interface within the particle is to date not fully understood. Here we attempt to gain understanding in these aspects through steered molecular dynamics simulation studies of water uptake by a vapor–hydroxy-cis-pinonic acid–water double interfacial system at 200 and 300 K. Simulated free-energy profiles are used to map the water uptake mechanism and are separated into energetic and entropic contributions to highlight its main thermodynamic driving forces. Atmospheric implications are discussed in terms of gas–particle partitioning, intraparticle water redistribution timescales and water vapor equilibrium saturation ratios. Our simulations reveal a strongly temperature-dependent water uptake mechanism, whose most prominent features are determined by local extrema in conformational and orientational entropies near the organic–water interface. This results in a low core uptake coefficient (ko/w=0.03) and a concentration gradient of water in the organic shell at the higher temperature, while entropic effects are negligible at 200 K due to the association-entropic-term reduction in the free-energy profiles. The concentration gradient, which results from non-ideal mixing – and is a major factor in increasing LLPS CCN activity – is responsible for maintaining liquid–liquid phase separation and low surface tension even at very high relative humidities, thus reducing critical supersaturations. Thermodynamic driving forces are rationalized to be generalizable across different compositions. The conditions under which single uptake coefficients can be used to describe growth kinetics as a function of temperature in LLPS particles are described.

Quest for the Molecular Basis of Improved Selective Toxicity of All-Trans Isomers of Aromatic Heptaene Macrolide Antifungal Antibiotics

Three aromatic heptaene macrolide antifungal antibiotics, Candicidin D, Partricin A (Gedamycin) and Partricin B (Vacidin) were subjected to controlled cis-trans ® all trans photochemical isomerization. The obtained all-trans isomers demonstrated substantially improved in vitro selective toxicity in the Candida albicans cells: human erythrocytes model. This effect was mainly due to the diminished hemotoxicity. The molecular modeling studies on interactions between original antibiotics and their photoisomers with ergosterol and cholesterol revealed some difference in free energy profiles of formation of binary antibiotic/sterol complexes in respective membrane environments. Moreover, different geometries of heptaene: sterol complexes and variations in polyene macrolide molecule alignment in cholesterol-and ergosterol-containing membranes were found. None of these effects are of the crucial importance for the observed improvement of selective toxicity of aromatic heptaene antifungals but each seems to provide a partial contribution.

A Bayesian approach to extracting free-energy profiles from cryo-electron microscopy experiments

Cryo-electron microscopy (cryo-EM) extracts single-particle density projections of individual biomolecules. Although cryo-EM is widely used for 3D reconstruction, due to its single-particle nature it has the potential to provide information about a biomolecule’s conformational variability and underlying free-energy landscape. However, treating cryo-EM as a single-molecule technique is challenging because of the low signal-to-noise ratio (SNR) in individual particles. In this work, we propose the cryo-BIFE method (cryo-EM Bayesian Inference of Free-Energy profiles), which uses a path collective variable to extract free-energy profiles and their uncertainties from cryo-EM images. We test the framework on several synthetic systems where the imaging parameters and conditions were controlled. We found that for realistic cryo-EM environments and relevant biomolecular systems, it is possible to recover the underlying free energy, with the pose accuracy and SNR as crucial determinants. We then use the method to study the conformational transitions of a calcium-activated channel with real cryo-EM particles. Interestingly, we recover not only the most probable conformation (used to generate a high-resolution reconstruction of the calcium-bound state) but also a metastable state that corresponds to the calcium-unbound conformation. As expected for turnover transitions within the same sample, the activation barriers are on the order of $$k_BT$$ k B T . We expect our tool for extracting free-energy profiles from cryo-EM images to enable more complete characterization of the thermodynamic ensemble of biomolecules.

Molecular scale description of interfacial mass transfer in phase separated aqueous secondary organic aerosol

Liquid-liquid phase separated (LLPS) aerosol particles are known to exhibit increased cloud condensation nuclei (CCN) activity compared to well mixed ones due to a complex effect of low surface tension and non-ideal mixing. The relation between the two contributions as well as the molecular scale mechanism of water uptake in the presence of an internal interface within the particle is to date not fully understood. Here we present steered molecular dynamics simulation studies of water uptake by a vapor/hydroxi-cis-pinonic acid/water double interfacial system at 200 K and 300 K. Simulated free energy profiles are used to map the water uptake mechanism and are decomposed into energetic and entropic contributions to highlight its main thermodynamic driving forces. Atmospheric implications are discussed in terms of gas/particle partitioning, intraparticle water redistribution timescales, and equilibrium saturation ratios of water vapor. Our simulations reveal a strongly temperature-dependent water uptake mechanism, whose most prominent features are determined by local extrema in conformational and orientational entropies near the organic/water interface which result in a reduced core uptake coefficient (ko/w = 0.05) and a concentration gradient of water in the organic shell at the higher temperature, while their effect is negligible at 200 K due to the explicit temperature dependence of entropic terms in the free energy profiles. The concentration gradient, which is a molecular level manifestation of non-ideal mixing – suspected to be a major factor to increase LLPS CCN activity – is responsible for maintaining LLPS and low surface tension even at very high relative humidities, thus reducing critical supersaturations. Thermodynamic driving forces are rationalised to be generalizable across different compositions. The conditions under which single uptake coefficients can be used to to describe growth kinetics as a function of temperature in LLPS particles are described.

Free energy landscape of RNA binding dynamics in start codon recognition by eukaryotic ribosomal pre-initiation complex

Specific interaction between the start codon, 5’-AUG-3’, and the anticodon, 5’-CAU-3’, ensures accurate initiation of translation. Recent studies show that several near-cognate start codons (e.g. GUG and CUG) can play a role in initiating translation in eukaryotes. However, the mechanism allowing initiation through mismatched base-pairs at the ribosomal decoding site is still unclear at an atomic level. In this work, we propose an extended simulation-based method to evaluate free energy profiles, through computing the distance between each base-pair of the triplet interactions involved in recognition of start codons in eukaryotic translation pre-initiation complex. Our method provides not only the free energy penalty for mismatched start codons relative to the AUG start codon, but also the preferred pathways of transitions between bound and unbound states, which has not been described by previous studies. To verify the method, the binding dynamics of cognate (AUG) and near-cognate start codons (CUG and GUG) were simulated. Evaluated free energy profiles agree with experimentally observed changes in initiation frequencies from respective codons. This work proposes for the first time how a G:U mismatch at the first position of codon (GUG)-anticodon base-pairs destabilizes the accommodation in the initiating eukaryotic ribosome and how initiation at a CUG codon is nearly as strong as, or sometimes stronger than, that at a GUG codon. Our method is expected to be applied to study the affinity changes for various mismatched base-pairs.

Reconstructing the Free Energy Profiles Describing the Switching Mechanism of a pH-Dependent DNA Nanodevice from ABMD Simulations

The pH-responsive behavior of six triple-helix DNA nanoswitches, differing in the number of protonation centers (two or four) and in the length of the linker (5, 15 or 25 bases), connecting the double-helical region to the single-strand triplex-forming region, was characterized at the atomistic level through Adaptively Biased Molecular Dynamics simulations. The reconstruction of the free energy profiles of triplex-forming oligonucleotide unbinding from the double helix identified a different minimum energy path for the three diprotic nanoswitches, depending on the length of the connecting linker and leading to a different per-base unbinding profile. The same analyses carried out on the tetraprotic switches indicated that, in the presence of four protonation centers, the unbinding process occurs independently of the linker length. The simulation data provide an atomistic explanation for previously published experimental results showing, only in the diprotic switch, a two unit increase in the pKa switching mechanism decreasing the linker length from 25 to 5 bases, endorsing the validity of computational methods for the design and refinement of functional DNA nanodevices.