Transparent Machine Learning Model to Understand Drug Permeability through the Blood-Brain Barrier.

The blood-brain barrier (BBB) selectively regulates the passage of chemical compounds into and out of the central nervous system (CNS). As such, understanding the permeability of drug molecules through the BBB is key to treating neurological diseases and evaluating the response of the CNS to medical treatments. Within the last two decades, a diverse portfolio of machine learning (ML) models have been regularly utilized as a tool to predict, and, to a much lesser extent, understand, several functional properties of medicinal drugs, including their propensity to pass through the BBB.

Data-driven discovery of potent small molecule ice recrystallisation inhibitors.

Controlling the formation and growth of ice is essential to successfully cryopreserve cells, tissues and biologics. Current efforts to identify materials capable of modulating ice growth are guided by iterative changes and human intuition, with a major focus on proteins and polymers. With limited data, the discovery pipeline is constrained by a poor understanding of the mechanisms and the underlying structure-activity relationships.

Contact-Map-Driven Exploration of Heterogeneous Protein-Folding Paths.

We have recently shown how physically realizable protein-folding pathways can be generated using directed walks in the space of inter-residue contact-maps; combined with a back-transformation to move from protein contact-maps to Cartesian coordinates, we have demonstrated how this approach can generate protein-folding trajectory ensembles without recourse to molecular dynamics. In this article, we demonstrate that this framework can be used to study a challenging protein-folding problem that is known to exhibit two different folding paths which were previously identified through molecular dynamics simulation at several different temperatures. From the viewpoint of protein-folding mechanism prediction, this particular problem is extremely challenging to address, specifically involving folding to an identical nontrivial compact native structure along distinct pathways defined by heterogeneous secondary structural elements.

Small molecule organic eutectics as candidates to replace plastics.

Legislative change and shifting consumer sentiment drive a need to replace polymers in certain products. Herein, we highlight that eutectic molecular glasses and liquids are promising but underutilized candidate materials. We formulate a series of hydrophobic eutectic molecular liquids and glasses by mixing their crystalline components.

Double Chalcogen Bonding Recognition Arrays in Solution.

N-substituted pyridino-based congeners of Ebselen, named here as Pyrselen, incorporating proximal Se and N atoms, undergo dimerization in solution and the solid state through a dual donor-acceptor arrangement of chalcogen bonding sites. Dimerization constants were measured within the 5-50 M range. Computational studies on the dimers depict a notable charge-transfer contribution to the association, validating Pyrselen as an effective scaffold for designing chalcogen-bonding-based recognition motifs.

Unravelling the interactions between small molecules and liposomal bilayers via molecular dynamics and thermodynamic modelling.

Lipid-based drug delivery systems hold immense promise in addressing critical medical needs, from cancer and neurodegenerative diseases to infectious diseases. By encapsulating active pharmaceutical ingredients - ranging from small molecule drugs to proteins and nucleic acids - these nanocarriers enhance treatment efficacy and safety. However, their commercial success faces hurdles, such as the lack of a systematic design approach and the issues related to scalability and reproducibility.

Understanding the impact of ammonium ion substitutions on heterogeneous ice nucleation.

Understanding the mechanisms underpinning heterogeneous ice nucleation in the presence of ionic inclusions is important for fields such as cryopreservation and for improved models of climate and weather prediction. Feldspar and ammonium are both present in significant quantities in the atmosphere, and experimental evidence has shown that feldspar can nucleate ice from ammonium-containing solutions at temperatures warmer than water alone. In recent work, Whale hypothesised that this increase in nucleation temperature is due to an increase in configurational entropy when an ammonium ion is included in the ice hydrogen bond network (T.

Combining machine learning and molecular simulations to predict the stability of amorphous drugs.

Amorphous drugs represent an intriguing option to bypass the low solubility of many crystalline formulations of pharmaceuticals. The physical stability of the amorphous phase with respect to the crystal is crucial to bring amorphous formulations into the market-however, predicting the timescale involved with the onset of crystallization a priori is a formidably challenging task. Machine learning can help in this context by crafting models capable of predicting the physical stability of any given amorphous drug.

Interplay of multiple clusters and initial interface positioning for forward flux sampling simulations of crystal nucleation.

Forward flux sampling (FFS) is a path sampling technique widely used in computer simulations of crystal nucleation from the melt. In such studies, the order parameter underpinning the progress of the FFS algorithm is often the size of the largest crystalline nucleus. In this work, we investigate the effects of two computational aspects of FFS simulations, using the prototypical Lennard-Jones liquid as our computational test bed.

Generating Protein Folding Trajectories Using Contact-Map-Driven Directed Walks.

Recent advances in machine learning methods have had a significant impact on protein structure prediction, but accurate generation and characterization of protein-folding pathways remains intractable. Here, we demonstrate how protein folding trajectories can be generated using a directed walk strategy operating in the space defined by the residue-level contact-map. This double-ended strategy views protein folding as a series of discrete transitions between connected minima on the potential energy surface.

Minimalistic ice recrystallisation inhibitors based on phenylalanine.

Ice recrystallisation inhibition (IRI) is typically associated with ice binding proteins, but polymers and other mimetics are emerging. Here we identify phenylalanine as a minimalistic, yet potent, small-molecule IRI capable of inhibiting ice growth at just 1 mg mL. Facial amphiphilicity is shown to be a crucial structural feature, with -substituents enhancing (hydrophobic) or decreasing (hydrophilic) IRI activity.

The role of structural order in heterogeneous ice nucleation.

The freezing of water into ice is a key process that is still not fully understood. It generally requires an impurity of some description to initiate the heterogeneous nucleation of the ice crystals. The molecular structure, as well as the extent of structural order within the impurity in question, both play an essential role in determining its effectiveness.

Lipid bilayers as potential ice nucleating agents.

Cellular damage is a key issue in the context of cryopreservation. Much of this damage is believed to be caused by extracellular ice formation at temperatures well above the homogeneous freezing point of pure water. Hence the question: what initiates ice nucleation during cryopreservation? In this paper, we assess whether cellular membranes could be responsible for facilitating the ice nucleation process, and what characteristics would make them good or bad ice nucleating agents.

How do interfaces alter the dynamics of supercooled water?

The structure of liquid water in the proximity of an interface can deviate significantly from that of bulk water, with surface-induced structural perturbations typically converging to bulk values at about ∼1 nm from the interface. While these structural changes are well established it is, in contrast, less clear how an interface perturbs the dynamics of water molecules within the liquid. Here, through an extensive set of molecular dynamics simulations of supercooled bulk and interfacial water films and nano-droplets, we observe the formation of persistent, spatially extended dynamical domains in which the average mobility varies as a function of the distance from the interface.

Ice Recrystallization Inhibition by Amino Acids: The Curious Case of Alpha- and Beta-Alanine.

Extremophiles produce macromolecules which inhibit ice recrystallization, but there is increasing interest in discovering and developing small molecules that can modulate ice growth. Realizing their potential requires an understanding of how these molecules function at the atomistic level. Here, we report the discovery that the amino acid l-α-alanine demonstrates ice recrystallization inhibition (IRI) activity, functioning at 100 mM (∼10 mg/mL).

The seven deadly sins: When computing crystal nucleation rates, the devil is in the details.

The formation of crystals has proven to be one of the most challenging phase transformations to quantitatively model-let alone to actually understand-be it by means of the latest experimental technique or the full arsenal of enhanced sampling approaches at our disposal. One of the most crucial quantities involved with the crystallization process is the nucleation rate, a single elusive number that is supposed to quantify the average probability for a nucleus of critical size to occur within a certain volume and time span. A substantial amount of effort has been devoted to attempt a connection between the crystal nucleation rates computed by means of atomistic simulations and their experimentally measured counterparts.

A minimalistic cyclic ice-binding peptide from phage display.

Developing molecules that emulate the properties of naturally occurring ice-binding proteins (IBPs) is a daunting challenge. Rather than relying on the (limited) existing structure-property relationships that have been established for IBPs, here we report the use of phage display for the identification of short peptide mimics of IBPs. To this end, an ice-affinity selection protocol is developed, which enables the selection of a cyclic ice-binding peptide containing just 14 amino acids.

Microscopic Kinetics Pathway of Salt Crystallization in Graphene Nanocapillaries.

The fundamental understanding of crystallization, in terms of microscopic kinetic and thermodynamic details, remains a key challenge in the physical sciences. Here, by using in situ graphene liquid cell transmission electron microscopy, we reveal the atomistic mechanism of NaCl crystallization from solutions confined within graphene cells. We find that rock salt NaCl forms with a peculiar hexagonal morphology.