Biology subjects

Moller, C.

Publications and source records attributed to Moller, C..

8 recordsLinked to original sources

bioRxiv2026

Programming N-linked glycan composition through de novo protein design

N-linked glycans are ubiquitous post-translational modifications that mediate diverse biological processes, including cell signaling and adhesion, molecular recognition, and host-pathogen interactions. Despite their importance, N-linked glycans have largely remained beyond the reach of biomolecular design due to a lack of methods capable of jointly modeling glycans and protein structure. Here, we develop a general all-atom computational pipeline for creating de novo glycoproteins in which the amino acid sequence encodes both the location and composition of N-linked glycans. The method uses three-dimensional protein structure to tune glycan accessibility to processing enzymes in the eukaryotic secretory pathway. Systematic increases in steric restriction progressively reduced processing, shifting glycans from heterogeneous complex-type structures toward increasingly underprocessed oligomannose-type species resembling those found on many viral glycoproteins. Despite this programmed restriction, the resulting oligomannose glycans remained accessible for biological recognition, inhibiting uropathogenic Escherichia coli adhesion to human bladder cells and binding mannose-binding lectin. These results establish steric control of N-glycan processing as a genetically encodable design principle and extend computational protein design to functional glycoproteins with programmed composition.

biochemistry↗

bioRxiv2026

De novo design of a macrocycle induced dimerization system for cellular control

Investigating and manipulating cellular events requires precise control of protein function. To enable control over cellular processes, we set out to design a chemically induced dimerization (CID) system consisting of a de novo designed ligand and protein pair. Here we describe the design of a C2 symmetric membrane permeable macrocyclic peptide and a cognate protein homodimer which binds the macrocycle through a large interface with both chains. The designed homodimer binds the macrocycle with a KD of 36 nM, and the x-ray crystal structure of the protein homodimer-macrocycle complex is very close to the computational design model, with the C2 axis of the macrocycle aligned with the homodimer C2 axis. Transcriptional and split luciferase assays in mammalian cells demonstrates conditional control over both a reporter gene expression and luciferase reconstitution.

biochemistry↗

bioRxiv2025

De novo design of phospho-tyrosine peptide binders

Phosphorylation on tyrosine is a key step in many signaling pathways. Despite recent progress in de novo design of protein binders, there are no current methods for designing binders that recognize phosphorylated proteins and peptides; this is a challenging problem as phosphate groups are highly charged, and phosphorylation often occurs within unstructured regions. Here we introduce RoseTTAFold Diffusion 2 for Molecular Interfaces (RFD2-MI), a deep generative framework for the design of binders for protein, ligand, and covalently modified protein targets. We demonstrate the power and versatility of this method by designing binders for four critical phosphotyrosine sites on three clinically relevant targets: Cluster of Differentiation 3 (CD3{varepsilon}), Epidermal Growth Factor Receptor (EGFR), Insulin Receptor (INSR) and Signal Transducer and Activator of Transcription 5 (STAT5). Experimental characterization shows that the designs bind their phosphotyrosine containing targets with affinities comparable to native binding sites and have negligible binding to non-phosphorylated targets or phosphopeptides with different sequences. X-ray crystal structures of generated binders to CD3{varepsilon} and EGFR are very close to the design models, demonstrating the accuracy of the design approach. A designed binder to an EGFR intracellular region phosphorylated upon EGF activation co-localizes with the receptor following EGF stimulation in single-particle tracking (SPT) experiments, demonstrating pY specific recognition in living cells. RFD2-MI provides a generalizable all-atom diffusion framework for probing and modulating phosphorylation-dependent signaling, and more generally, for developing research tools and targeted therapeutics against post-translationally modified proteins.

bioengineering↗

bioRxiv2024

Trade-offs between averages and intra-individual variation within vegetative, phenological, and floral traits

O_LIIntra-individual trait variation in plants represents an often ignored but important dimension of phenotypic variation that contributes to functional diversity and the dynamics of ecological communities. It can be expressed differently across plant traits, but the induction of intra-individual variation in different trait types under environmental stresses has not yet been explored. C_LIO_LIWe used the clonal forest herb, Galium odoratum, to investigate intra-individual variation within vegetative, phenological, and floral traits, and trade-offs between trait average and variation under a full-factorial experimental design using drought and shading treatments. C_LIO_LIIntra-individual variation (expressed as CV) differed in magnitude between trait types, with vegetative and floral traits showing the highest and lowest CV, respectively. CV occurring in the different traits responded to the drought and shade treatments. Trade-offs between CV and trait averages appeared across most of traits under the different treatment combinations, whereas trade-offs were less pronounced under control conditions. C_LIO_LIDrought and shading in forest environments induce trade-offs between intra-individual variation and the average trait expression, indicating the relevance of intra-individual variation for functional adaptations of forest plants to climatic changes. Our findings suggest that plastic responses in intra-individual variation may be an important component for mechanistic adjustments of plants to environmental stresses. C_LI

evolutionary biology↗

bioRxiv2021

Beat Perception in Polyrhythms: Time is Structured in Binary Units

In everyday life, we group and subdivide time to understand the sensory environment surrounding us. Our perceptual system establishes hierarchical structures by nesting different groups of time intervals. Organizing time in units such as diurnal rhythms, phrases, and beat patterns, is fundamental to everyday behavior, speech, and music. When listening to music, we extract rhythmic regularities to create a hierarchical metrical structure that enables us to predict the timing of the next events. Foot tapping and head bobbing to musical rhythms are observable evidence of this process. In the special case of polyrhythms, at least two metrical structures compete to become the reference for these temporal regularities, rendering several possible beats with which we can synchronize our movements. While there is general agreement that tempo, pitch, and loudness influence beat perception in polyrhythms, we focused on the yet neglected influence of beat subdivisions. In three online experiments, 300 participants listened to a range of polyrhythms and tapped their index fingers in time with the perceived beat. The polyrhythms consisted of two simultaneously presented isochronous pulse trains with different ratios (2:3, 2:5, 3:4, 3:5, 4:5, 5:6) and different tempi. For ratios 2:3 and 3:4, we additionally manipulated the pitch of the pulse trains. Results showed a highly robust influence of subdivision grouping on beat perception manifested as a propensity towards beats that are subdivided into two or four equally spaced units, as opposed to beats with three or more complex groupings of subdivisions. Additionally, lower pitched pulse trains were more likely to be perceived as the beat. Our findings suggest that subdivisions, not beats, are the basic unit of beat perception, and that the principle underlying the binary grouping of subdivisions reflects a propensity towards simplicity. This preference for simple grouping is widely applicable to human perception and cognition of time.

neuroscience↗

bioRxiv2020

Identification of SARS-CoV2-mediated suppression of NRF2 signaling reveals a potent antiviral and anti-inflammatory activity of 4-octyl-itaconate and dimethyl fumarate

Antiviral strategies to inhibit Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV2) and the pathogenic consequences of COVID-19 are urgently required. Here we demonstrate that the NRF2 anti-oxidant gene expression pathway is suppressed in biopsies obtained from COVID-19 patients. Further, we uncover that NRF2 agonists 4-octyl-itaconate (4-OI) and the clinically approved dimethyl fumarate (DMF) induce a cellular anti-viral program, which potently inhibits replication of SARS-CoV2 across cell lines. The anti-viral program extended to inhibit the replication of several other pathogenic viruses including Herpes Simplex Virus-1 and-2, Vaccinia virus, and Zika virus through a type I interferon (IFN)-independent mechanism. In addition, induction of NRF2 by 4-OI and DMF limited host inflammatory responses to SARS-CoV2 infection associated with airway COVID-19 pathology. In conclusion, NRF2 agonists 4-OI and DMF induce a distinct IFN-independent antiviral program that is broadly effective in limiting virus replication and suppressing the pro-inflammatory responses of human pathogenic viruses, including SARS-CoV2. One Sentence SummaryNRF2 agonists 4-octyl-itaconate (4-OI) and dimethyl fumarate inhibited SARS-CoV2 replication and virus-induced inflammatory responses, as well as replication of other human pathogenic viruses.

microbiology↗

bioRxiv2019

Poorer auditory sensitivity is related to stronger visual enhancement of the human auditory mismatch negativity (MMNm)

Multisensory processing facilitates perception of our everyday environment and becomes particularly important when sensory information is degraded or close to the discrimination threshold. Here, we used magnetoencephalography and an audiovisual oddball paradigm to assess the complementary role of visual information in subtle pitch discrimination at the neural level of participants with varying levels of pitch discrimination abilities, i.e., musicians and nonmusicians. The amplitude of the auditory mismatch negativity (MMNm) served as an index of sensitivity. The gain in amplitude resulting from compatible audiovisual information was larger in participants whose MMNm amplitude was smaller in the condition deviating only in the auditory dimension, in accordance with the multisensory principle of inverse effectiveness. These findings show that discrimination of even a sensory-specific feature as pitch is facilitated by multisensory information at a pre-attentive level, and they highlight the importance of considering inter-individual differences in uni-sensory abilities when assessing multisensory processing.

neuroscience↗

bioRxiv2019

Domain-relevant auditory expertise modulates the additivity of neural mismatch responses in humans

It is unknown whether domain-relevant expertise is associated with more independent or more dependent predictive processing of acoustic features. Here, mismatch negativity (MMNm) was recorded with magnetoencephalography (MEG) from 25 musicians and 25 non-musicians, exposed to complex musical multi-feature and simple oddball control paradigms. Deviants differed in frequency (F), intensity (I), perceived location (L), or any combination of these (FI, IL, LF, FIL). Neural processing overlap was assessed through MMNm additivity by comparing double- and triple-deviant MMNms ("empirical") to summed constituent single-deviant MMNms ("modelled"). Significantly greater subadditivity was present in musicians compared to non-musicians, specifically for frequency-related deviants in complex contexts. Despite using identical sounds, expertise effects were absent from the simple paradigm. This novel finding supports the dependent processing hypothesis whereby experts recruit overlapping neural resources facilitating more integrative representations of domain-relevant stimuli. Such specialized predictive processing may enable experts such as musicians to capitalise on complex acoustic cues.

neuroscience↗