Biology subjects

Ulmschneider, M. B.

Publications and source records attributed to Ulmschneider, M. B..

4 recordsLinked to original sources

bioRxiv2025

Structural Impact of Alzheimer's Disease Mutations on Transmembrane TREM2-DAP12 Interactions: An Atomistic Perspective

Triggering receptor expressed on myeloid cells 2 (TREM2) is an immunomodulatory receptor that plays a critical role in microglial activation through its association with the adaptor protein DNAX-activation protein 12 (DAP12). Genetic studies have identified rare TREM2 variants as key risk factors for Alzheimers disease (AD), with mutations affecting both the extracellular and transmembrane domains. While the TREM2-DAP12 complex is essential for microglial activation and is implicated in Alzheimers disease pathology, the structural and mechanistic effects of transmembrane domain mutations, particularly within different TREM2 isoforms, remain unclear. In this study, we employ multi-scale molecular dynamics simulations to investigate the impact of six TREM2 mutations (four in isoform 1, two in isoform 2) and one wild-type control (isoform 2) on complex stability. By integrating coarse-grain and all-atom simulations with unsupervised machine learning techniques, we reveal distinct conformational states and residue-level interactions that govern complex formation. Our findings demonstrate how mutations such as W191X in TREM2 isoform 2 disrupt critical interactions, leading to destabilisation of the complex and potential impairments in neuroimmune signalling. These results provide new insights into the structural mechanisms linking TREM2 mutations to AD and offer a foundation for developing targeted therapeutic strategies.

biophysics↗

bioRxiv2025

A bio-informatics approach to identify new drug targets in multidrug-resistant bacteria

Antibiotic resistance poses a global health crisis. In order to develop new antibiotic agents, it is crucial to identify drug targets in multidrug-resistant bacteria. Criteria for such a target are an -helical, essential membrane protein, that is non-homologues with the human membrane proteome, and present across multiple bacterial species. Using a stepwise subtractive genomics approach, the membrane protein F0F1 ATP synthase subunit C was identified as a non-human analogues drug target that is present in 11 bacterial species.

bioinformatics↗

bioRxiv2024

Novel gramicidin-derived ????-helical antimicrobialpeptides

Combating the threat of multidrug resistance bacteria requires many different approaches. Using structural motifs and sequences from existing antibacterial compounds affords a fresh attack against such bacteria, while circumventing inherited resistance against the existing compound. Gramicidin is a 16 amino acid peptide with an alternating O_SCPLOWLC_SCPLOW- and O_SCPLOWDC_SCPLOW-motif with highly bacteriocidal effects in gram-positive membranes. In the membrane it assumes a {beta}-helix form with two peptides aligned by their N-terminal interactions, and only conducts in such a form. Using gramicidin as a basis, this study employs molecular dynamics simulations as an initial design step and evaluates gramicidin-derived candidates based on their backbone hydrogen-bond interactions, capacity for conductance, profile of their RMSD over the course of the simulation, and how the peptide interacts with the phospholipid headgroups. There are twelve candidate systems with results comparable to gramicidin and the factors at play in their efficacy are examined.

biophysics↗

bioRxiv2020

Rational tuning of a membrane-perforating antimicrobial peptide to selectively target membranes of different lipid composition

The use of designed antimicrobial peptides as drugs has been impeded by the absence of simple sequence-structure-function relationships and design rules. The likely cause is that many of these peptides permeabilize membranes via highly disordered, heterogeneous mechanisms, forming aggregates without well-defined tertiary or secondary structure. We demonstrate that the combination of high-throughput library screening with atomistic computer simulations can successfully address this challenge by tuning a previously developed general pore forming peptide into a selective pore former for different lipid types. A library of 2,916 peptides was designed based on the LDKA template. The library peptides were synthesized and screened using a high-throughput orthogonal vesicle leakage assay. Dyes of different sizes were entrapped inside vesicles with varying lipid composition to simultaneously screen for both pore size and affinity for negatively charged and neutral lipid membranes. From this screen, nine different LDKA variants that have unique activity were selected, sequenced, synthesized, and characterized. Despite the minor sequence changes, each of these peptides has unique functional properties, forming either small or large pores and being selective for either neutral or anionic lipid bilayers. Long-scale, unbiased atomistic molecular dynamics (MD) simulations directly reveal that rather than rigid, well-defined pores, these peptides can form a large repertoire of functional dynamic and heterogeneous aggregates, strongly affected by single mutations. Predicting the propensity to aggregate and assemble in a given environment from sequence alone holds the key to functional prediction of membrane permeabilization.

biochemistry↗