Schizophrenia-associated somatic copy-number variants from 12,834 cases reveal recurrent NRXN1 and ABCB11 disruptions

While germline copy-number variants (CNVs) contribute to schizophrenia (SCZ) risk, the contribution of somatic CNVs (sCNVs)—present in some but not all cells—remains unknown. We identified sCNVs using blood-derived genotype arrays from 12,834 SCZ cases and 11,648 controls, filtering sCNVs at loci recurrently mutated in clonal blood disorders. Likely early-developmental sCNVs were more common in cases (0.91%) than controls (0.51%, p = 2.68e−4), with recurrent somatic deletions of exons 1–5 of the NRXN1 gene in five SCZ cases. Hi-C maps revealed ectopic, allele-specific loops forming between a potential cryptic promoter and non-coding cis-regulatory elements upon 5′ deletions in NRXN1. We also observed recurrent intragenic deletions of ABCB11, encoding a transporter implicated in anti-psychotic response, in five treatment-resistant SCZ cases and showed that ABCB11 is specifically enriched in neurons forming mesocortical and mesolimbic dopaminergic projections. Our results indicate potential roles of sCNVs in SCZ risk

Connecting dynamic reweighting Algorithms: Derivation of the dynamic reweighting family tree

Thermally driven processes of molecular systems include transitions of energy barriers on the microsecond timescales and higher. Sufficient sampling of such processes with molecular dynamics simulations is challenging and often requires accelerating slow transitions using external biasing potentials. Different dynamic reweighting algorithms have been proposed in the past few years to recover the unbiased kinetics from biased systems. However, it remains an open question if and how these dynamic reweighting approaches are connected. In this work, we establish the link between the two main reweighting types, i.e., path-based and energy-based reweighting. We derive a path-based correction factor for the energy-based dynamic histogram analysis method, thus connecting the previously separate reweighting types. We show that the correction factor can be used to combine the advantages of path-based and energy-based reweighting algorithms: it is integrator independent, more robust, and at the same time able to reweight time-dependent biases. We can furthermore demonstrate the relationship between two independently derived path-based reweighting algorithms. Our theoretical findings are verified on a one-dimensional four-well system. By connecting different dynamic reweighting algorithms, this work helps to clarify the strengths and limitations of the different methods and enables a more robust usage of the combined types.ISSN:0021-9606ISSN:1089-769

Enhanced sampling without borders: on global biasing functions and how to reweight them

Molecular dynamics (MD) simulations are a powerful tool to follow the time evolution of biomolecular motions in atomistic resolution. However, the high computational demand of these simulations limits the timescales of motions that can be observed. To resolve this issue, so called enhanced sampling techniques are developed, which extend conventional MD algorithms to speed up the simulation process. Here, we focus on techniques that apply global biasing functions. We provide a broad overview of established enhanced sampling methods and promising new advances. As the ultimate goal is to retrieve unbiased information from biased ensembles, we also discuss benefits and limitations of common reweighting schemes. In addition to concisely summarizing critical assumptions and implications, we highlight the general application opportunities as well as uncertainties of global enhanced sampling.ISSN:1463-9084ISSN:1463-907

Passing the barrier – How computer simulations can help to understand and improve the passive membrane permeability of cyclic peptides

Proteins with large and flat binding sites as well as protein–protein interactions are considered ' undruggable ' with conventional small-molecule drugs. Cyclic peptides have been found to be capable of binding to such targets with high affinity, making this class of compounds an interesting source for possible therapeutics. However, the oftentimes poor passive membrane permeability of cyclic peptides still imposes restrictions on the applicability of cyclic peptide drugs. Here, we describe how computational methods in combination with experimental data can be used to improve our understanding of the structure–permeability relationship. Especially the conformational dynamic and chameleonic nature of cyclic peptides, which we investigate by a combination of MD simulations and kinetic modeling, is important for their ability to permeate passively through the membrane. The insights from such studies may enable the formulation of design principles for the rational design of permeable cyclic peptides.ISSN:0009-429

Ensembler: A Simple Package for Fast Prototyping and Teaching Molecular Simulations

Ensembler is a Python package that enables method prototyping using 1D and 2D model systems and allows deepening of the understanding of different molecular dynamics (MD) methods, starting from basic techniques to enhanced sampling and free-energy approaches. The ease of installing and using the package increases shareability, comparability, and reproducibility of scientific code developments. Here, we describe the implementation and usage of the package and provide an application example for free-energy calculation. The code of Ensembler is freely available on GitHub at https://github.com/rinikerlab/Ensembler.ISSN:1549-9596ISSN:0095-2338ISSN:1520-514

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ISSN:0009-429

Carbon Nanotubes Mediate Fusion of Lipid Vesicles

The fusion of lipid membranes is opposed by high energetic barriers. In living organisms, complex protein machineries carry out this biologically essential process. Here we show that membrane-spanning carbon nanotubes (CNTs) can trigger spontaneous fusion of small lipid vesicles. In coarse-grained molecular dynamics simulations, we find that a CNT bridging between two vesicles locally perturbs their lipid structure. Their outer leaflets merge as the CNT pulls lipids out of the membranes, creating an hourglass-shaped fusion intermediate with still intact inner leaflets. As the CNT moves away from the symmetry axis connecting the vesicle centers, the inner leaflets merge, forming a pore that completes fusion. The distinct mechanism of CNT-mediated membrane fusion may be transferable, providing guidance in the development of fusion agents, <i>e.g.</i>, for the targeted delivery of drugs or nucleic acids

Lessons for Oral Bioavailability: How Conformationally Flexible Cyclic Peptides Enter and Cross Lipid Membranes

Cyclic peptides are able to extend the druggable space of pharmaceutical targets, due to their size, conformational behavior, and high proportion of hydrogen bond donors and acceptors. However, for the same reasons, they often suffer from poor membrane permeation and thus low oral bioavailability. As permeability assays do not allow to monitor the pathway and behavior of cyclic peptides on their “journey” trough lipid membranes, little is known about the underlying permeation process, which poses a major obstacle for their rational design. Here, we use molecular dynamics (MD) simulations as a computational microscope to uncover how large and conformationally flexible cyclic peptides enter and cross a lipid bilayer. In a first step, we performed unbiased MD simulations to elucidate the permeation pathway. Subsequently, this pathway knowledge was utilized to seed biased simulations to further enrich for permeation events. Based on our simulations, we show how specific side-chain residues can act as ’molecular anchors’, which establish the first contact between the peptides and the membrane, and consequently enable membrane insertion. Inside the membrane, the cyclic peptides are positioned directly between the polar headgroup and the apolar tail region, where they are subjected to a unique polar/apolar interface environment. In this environment, the cyclic peptides show a preference for one of two distinct orientations. We observe that only one of these orientations allows the formation of the permeable ’closed’ conformation, and only in this ’closed’ conformation the cyclic peptides can cross from the upper to the lower membrane leaflet, which again requires a unique anchoring and flipping mechanism. Our findings provide atomistic insights into the permeation process of flexible cyclic peptides and reveal unique design considerations for each step of the process