Biology subjects

Poma, A.

Publications and source records attributed to Poma, A..

6 recordsLinked to original sources

bioRxiv2026

Structural modelling and biophysical analyses reveal a dimeric coiled-coil architecture in the FAZ10 central region of Trypanosoma brucei

Trypanosoma brucei relies on the flagellum attachment zone (FAZ) to coordinate flagellum positioning, cell morphology, and cytokinesis. The giant FAZ10 protein, which contains both repetitive and structured regions, is essential for correct cleavage-furrow placement, yet its molecular organization remains unresolved due to its exceptional size. In this study, we define the architecture of the FAZ10 central region through structural modelling and biophysical validation. AlphaFold2 and molecular dynamics simulations defined a parallel coiled-coil dimer flanked by symmetric globular domains, with canonical hydrophobic core packing, complementary interhelical contacts, and local heptad discontinuities, including a stammer-stutter pair that modulates the superhelical geometry. Biophysical analyses show that this region forms a stable dimer in solution, mediated by the coiled-coil domain and consistent with a predominantly -helical structure. Together, these findings identify the FAZ10 central region as a semi-flexible dimeric scaffold that provides a structural framework for understanding FAZ supramolecular organization and the integration of large cytoskeletal assemblies in trypanosomatids.

biophysics↗

bioRxiv2025

An optimized contact map for GoMartini 3 enabling conformational changes in protein assemblies

Advances in structural biology, particularly cryo-electron microscopy, have enabled high-resolution characterization of complex biomolecular assemblies. These developments emphasize the need for computational approaches capable of describing biologically relevant conformational changes over extended timescales. G[o]Martini 3 is a coarse-grained approach that demonstrates computational efficiency and versatility across several systems, from protein-binding membranes and soluble proteins to intrinsically disordered proteins, while preserving key physicochemical features. In this work, we introduce an optimized approach that integrates dynamic contact information from AA-MD simulations to refine the contact map in G[o]Martini simulations. Specifically, we define high-frequency contacts (HFC), which reduce the number of original G[o] contacts set by {approx}20-30%, thereby improving the representation of conformational states beyond the original approach. Benchmarking different contact-selection criteria revealed that including intra- and interchain HFC captures structural flexibility and domain dynamics. The method was tested on three small soluble proteins and on the SARS-CoV-2 spike protein. Overall, the optimized contact map improves sampling efficiency and expands the accessible conformational landscape relative to the original G[o]Martini 3 implementation. The full framework is available as an open-source resource for large-scale simulations of biomolecular assemblies.

biophysics↗

bioRxiv2021

Targeting activated macrophages intracellular milieu to augment anti-inflammatory drug potency

We present pH-responsive phosphorylcholine polymersomes ability to target activated macrophages via scavenger receptors, enter them via endocytosis, and escape from early endosomes enabling the intra-cellular drug delivery. Using an arthritis experimental model and the gold standard disease modifying anti-rheumatic drug, methotrexate, we prove that polymersomes augments therapeutic efficacy, while minimizing the off-target effect. First, we demonstrate the selective accumulation of polymersomes within the inflamed synovial tissues and cells, including macrophages. Second, we show the beneficial therapeutic effect of methotrexate loaded polymersomes in preventing both joint inflammation and further damage. Hence, we prove the therapeutic potential of polymersomes in enhancing the complete prevention of arthritis progression, which makes it a promising nanotherapy for arthritis treatment as well as other inflammatory disorders. TeaserWe show that the effective targeting and delivery of drugs to the main inflammation actors, the macrophages, enhances arthritis therapy.

immunology↗

bioRxiv2020

On the shuttling across the blood-brain barrier via tubules formation: mechanism and cargo avidity bias

The blood-brain barrier is made of polarised brain endothelial cells (BECs) phenotypically conditioned by the central nervous system (CNS). Transport across BECs is of paramount importance for nutrient uptake as well as to rid the brain of waste products. Nevertheless, currently we do not understand how large macromolecular cargo shuttles across and how BECs discriminate between the brain-bound and own nutrients. Here, we study the low-density lipoprotein receptor-related protein 1 (LRP1) an essential regulator of BEC transport, and show that it is associated with endocytic effectors, endo-lysosomal compartments as well as syndapin-2, a member of the Bin/Amphiphysin/Rvs (BAR) domain superfamily known to stabilise tubular carriers. We employed synthetic self-assembled vesicles, polymersomes, as a multivalent system with tunable avidity as a tool to investigate the mechanism of transport across BECs. We used a combination of conventional and super-resolution microscopy, both in vivo and in vitro, accompanied with biophysical modelling of transport kinetics and membrane-bound interactions. Our results demonstrate that the avidity of the ligand-receptor interaction (the overall cargo binding energy) determines the mechanism of sorting during the early stages of endocytosis and consequent trafficking. We show that high avidity cargo biases the LRP1 towards internalisation and fast degradation in BECs, while mid avidity augments the formation of syndapin-2 stabilised tubular carriers and promotes fast shuttling across BECs. Thus, we map out a very detailed mechanism where clathrin, actin, syndapin-2, dynamin and SNARE act synergistically to enable fast shuttling across BECs.

neuroscience↗

bioRxiv2019

Mechanical and thermodynamic properties of Aβ42, Aβ40 and α-synuclein fibrils: A coarse-grained method to complement experimental studies

We perform molecular dynamics simulation on several relevant biological fibrils associated with neurodegenerative diseases such as A{beta}40, A{beta}42, and the {beta}-synuclein systems to obtain a molecular understanding and interpretation of nanomechanical characterization experiments. The computational method is versatile and addresses a new subarea within the mechanical characterization of heterogeneous soft materials. We investigate both the elastic and thermodynamic properties of the biological fibrils in order to substantiate experimental nanomechanical characterization techniques that are quickly developing and reaching dynamic imaging with video rate capabilities. The computational method qualitatively reproduces results of experiments with biological fibrils, validating its use in extrapolation to macroscopic material properties. Our computational techniques can be used for the co-design of new experiments aiming to unveil nanomechanical properties of biological fibrils from a molecular understanding point of view. Our approach allows a comparison of diverse elastic properties of the latter fibrils, which enables the detailed analysis of the mechanical response at the molecular level. For these systems, the simulation approach indicates qualitative agreement with the experimental estimations of the elastic moduli for three different types of deformation, i.e. tensile (YL), shear (S), and indentation (YT ). From our analysis, we find a significant elastic anisotropy between axial and transverse directions (i.e. YT>YL) for all systems. Interestingly, our results indicate a higher mechanostability in the case of A{beta}42 fibrils than in the case of {beta}40, suggesting a significant correlation between mechanical stability and aggregation propensity (rate) in amyloid systems, that is, the higher the mechanical stability the faster the fibril formation. Finally, we find that -synuclein fibrils are thermally less stable than {beta}-amyloid fibrils. We anticipate that our molecular-level analysis of the mechanical response under different deformation conditions for the range of fibrils considered here will provide significant insights for the experimental observations.

biophysics↗

bioRxiv2017

Polymersomes Targeting Mononuclear Phagocytes

Mononuclear phagocytes such as monocytes, tissue-specific macrophages and dendritic cells are primary actors in both innate and adaptive immunity, as well as tissue homoeostasis. They have key roles in a range of physiological and pathological processes, so any strategy targeting these cells will have wide-ranging impact. These phagocytes can be parasitized by intracellular bacteria, turning them from housekeepers to hiding places and favouring chronic and/or disseminated infection. One of the most infamous is the bacteria that cause tuberculosis, which is the most pandemic and one of the deadliest disease with one third of the worlds population infected, and 1.8 million deaths worldwide in 2015. Here we demonstrate the effective targeting and intracellular delivery of antibiotics to both circulating monocytes and resident macrophages, using pH sensitive nanoscopic polymersomes made of poly(2-(methacryloyloxy)ethyl phosphorylcholine)-co-poly(2-(di-isopropylamino)ethyl methacrylate) (PMPC-PDPA). Polymersome selectivity to mononuclear phagocytes is demonstrated and ascribed to the polymerised phosphorylcholine motifs affinity toward scavenger receptors. Finally, we demonstrate the successful exploitation of this targeting for the effective eradication of intracellular bacteria that cause tuberculosis Mycobacterium tuberculosis as well as other intracellular parasites including the Mycobacterium bovis, Mycobacterium marinum and the most common bacteria associated with antibiotic resistance, the Staphylococcus aureus.

immunology↗