Biology subjects

Motta, S.

Publications and source records attributed to Motta, S..

4 recordsLinked to original sources

bioRxiv2026

Spatiotemporal graph neural networks reveal conformational binding signature in protein dynamics

Biomolecular function is often controlled by structural and dynamical adaptations to binding events. Although molecular dynamics (MD) simulations can capture these events at atomic resolution, separating functional signatures from stochastic noise remains challenging. Traditional methods often struggle to isolate mechanistically relevant differences across independent replicas. Here, we introduce an explainable deep learning approach that learns state-specific dynamic signatures directly from MD trajectories. By coupling a dynamic protein graph representation with group-aware contrastive learning across independent replicas, the model detects the signatures, filtering out trajectory-specific correlations. An explainable AI framework then maps the identified differences on individual residues. We demonstrate this approach by identifying "binding-ready" conformations in a T4-Lysozyme mutant, recovering the allosteric determinants of peptide recognition in the PDZ3 domain, and isolating a ligand-independent activation signature for the A2A receptor. Our GISTnet-MD method generalizes across unseen data during comparative MD analysis, translating raw trajectory differences into residue-level determinants of protein function.

biophysics↗

bioRxiv2025

Distinct 2-phenyl-imidazo pyridine derivatives drive ER degradation and selectively impair proliferation of ER+ breast cancer cells via the aryl hydrocarbon receptor

X15695 is a 2-phenyl-imidazo[1, 2] pyridine derivative identified as an orally active, selective oestrogen receptor (ER) degrader that inhibits the proliferation of ER+ breast cancer cells. Here, we show that X15695 is an aryl hydrocarbon receptor (AHR) ligand that stabilises the AHR more efficiently than its classical ligand, indirubin. X15695 enables AHR to form a complex with the ER, promoting its proteasomal degradation. In the presence of oestradiol, X15695 outperforms the standard of care drug fulvestrant in suppressing the growth of ER+ breast cancer cells, either expressing the wild-type or clinically relevant ER mutant forms (Y537S and D538G), and of patient-derived xenograft organoids established from ER+ tumours. Using computational techniques, we discovered that a low pKa value resulting from electron-withdrawing substituents in the 2-phenyl-imidazo[1, 2] pyridine compounds is a key feature that identify them as potent AHR ligands, leading to the potential discovery of additional derivatives for future therapeutic development.

cancer biology↗

bioRxiv2020

Unveiling diffusion pattern and structural impact of the most invasive SARS-CoV-2 spike mutation

Starting in Wuhan, China, SARS-CoV-2 epidemics quickly propagated worldwide in less than three months, geographically sorting genomic variants in newly established propagules of infections. Stochasticity in transmission within and between countries and/or actual advantage in virus transmissibility could explain the high frequency reached by some genomic variants during the course of the outbreak. Using a suite of statistical, population genetics, and theoretical approaches, we show that the globally most represented spike protein variant (i.e., the G clade, A [->] G nucleotide change at genomic position 23,403; D [->] G amino acid change at spike protein position 614) i) underwent a significant demographic expansion in most countries not explained by stochastic effects or enhanced pathogenicity; ii) affects the spike S1/S2 furin-like site increasing its conformational plasticity (short range effect), and iii) modifies the internal motion of the receptor-binding domain affecting its cross-connection with other functional domains (long-range effect). Our study unambiguously links the spread of the G614 with a non-random process, and we hypothesize that this process is related to the selective advantage produced by a specific structural modification of the spike protein. We conclude that the different conformation of the S1/S2 proteolytic site is at the basis of the higher transmission rate of this invasive SARS-CoV-2 variant, and provide structural information to guide the design of selective and efficient drugs.

evolutionary biology↗

bioRxiv2020

The distribution of functional N-cycle related genes and nitrogen in soil profiles fertilized with mineral and organic N fertilizer

Nitrogen (N) fertilizers applied to agricultural soils result in the release of nitrogen, mainly nitrate (NO3-) in addition to nitrous oxide (N2O) and ammonia (NH3), into the environment. Nitrogen transformation in soil is a complex process and the soil microbial population can regulate the potential for N mineralization, nitrification and denitrification. Here we show that agricultural soils under standard agricultural N-management are consistently characterized by a high presence of gene copies for some of the key biological activities related to the N-cycle. This led to a strong NO3- reduction (75%) passing from the soil surface (15.38 {+/-} 11.36 g N-NO3 kg-1 on average) to 1 m deep layer (3.92 {+/-} 4.42 g N-NO3 kg-1 on average), and ensured low nitrate presence in the deepest layer. Under these circumstances the other soil properties play a minor role in reducing soil nitrate presence in soil. However, with excessive N fertilization, the abundance of bacterial gene copies is not sufficient to explain N leaching in soil and other factors, i.e. soil texture and rainfall, become more important in controlling these aspects.

ecology↗