Biology subjects

Bartocci, A.

Publications and source records attributed to Bartocci, A..

4 recordsLinked to original sources

bioRxiv2026

MD simulations of Human Sigma1 Receptor Trimer Uncovers Cholesterol Dependent Stabilization and Ligand Specific Dynamics

The sigma-1 receptor (S1R) is an endoplasmic reticulum transmembrane protein implicated in a wide range of physiological and pathological processes, including neurodegeneration, cancer, and pain modulation. Although X-ray crystallography has revealed S1R as a trimeric assembly with a distinctive triangular architecture, the dynamic behavior of this oligomeric state and its modulation by ligands and membrane composition remain poorly understood. In particular, agonists and antagonists have been experimentally proved to differentially regulate S1R oligomerization although the underlying molecular mechanisms are still obscure. Here, we present the first atomistic molecular dynamics study of trimeric S1R embedded in a physiologically relevant lipid environment. Using a total of 12 {micro}s of simulation time, we investigate the impact of membrane composition, with a specific focus on cholesterol, as well as the conformational response of S1R to pharmacologically distinct ligands: the agonist (+)-pentazocine and the antagonist haloperidol. Our simulations reveal how ligands can alter S1R interprotomer interaction through a mechanism involving the {beta}6-strand of the protein and in particular W136, data that correlate with experimentally observed differences in S1R oligomerization. These findings provide new molecular-level insights into S1R regulation and establish a framework for rationalizing the distinct functional outcomes induced by agonists and antagonists.

pharmacology and toxicology↗

bioRxiv2024

A common haplotype in the EXO5 gene can impact its protein structure and dynamics and modulate genome stability and cancer progression

Understanding the impact of common germline variants on protein structure, function, and disease progression is crucial in cancer research. This study presents a comprehensive analysis of the EXO5 gene, which encodes a DNA exonuclease involved in DNA repair previously associated with cancer susceptibility. We employed an integrated approach combining genomic and clinical data analysis, deep learning variant effect prediction, and molecular dynamics simulations to investigate the effects of common EXO5 haplotypes on protein structure, dynamics, and cancer outcomes. We characterized the haplotype structure of EXO5 across diverse human populations, identifying five common haplotypes, and studied their impact on EXO5 protein. Our analyses revealed significant structural and dynamic differences among the EXO5 haplotypes, particularly in their catalytic region. The L151P EXO5 protein variant exhibited the most substantial conformational changes, potentially disruptive for EXO5s function and nuclear localization. Analysis of TCGA data showed that patients carrying L151P EXO5 had significantly shorter progression-free survival in prostate and pancreatic cancers, and exhibited increased genomic instability. This study highlights the strength of our methodology in uncovering the effects of common genetic variants on protein function and their implications for disease outcomes.

bioinformatics↗

bioRxiv2023

A computational study to assess the pathogenicity of single or combinations of missense variants on respiratory Complex I

Variants found in the respiratory complex I (CI) subunit genes encoded by mitochondrial DNA can cause severe genetic diseases. However, it is difficult to establish a priori whether a single or a combination of CI variants may impact oxidative phosphorylation. Here we propose a computational approach based on coarse-grained molecular dynamics simulations. One of the primary CI variants (m.14484T>C/MT-ND6) associated with the Leber hereditary optic neuropathy was used as a test case. This variant was investigated alone or in combination with two additional rare CI variants whose role remains uncertain. We found that the primary variant stiffens CI dynamics in the crucial E-channel region and that one of the other variants, located in the vicinity of the primary one, further worsens the stiffening. This approach may be extended to other variants candidate to exert a pathogenic impact on CI function, or to investigate the interaction of multiple variants. TeaserMolecular dynamics is able to predict the functional impact of variants hitting respiratory complex I mitochondrial genes.

biophysics↗

bioRxiv2023

A millisecond coarse-grained simulation approach to decipher allosteric cannabinoid binding at the glycine receptor α1

Glycine receptors (GlyR) are regulated by small-molecule binding at several allosteric sites. Cannabinoids like tetrahydrocannabinol (THC) and N-arachidonyl-ethanol-amide (AEA) potentiate GlyR but their mechanism of action is not fully established. By combining millisecond coarse-grained MD simulations powered by Martini 3 with backmapping to all-atom representations, we characterize the cannabinoid-binding sites at zebrafish GlyR-1 with atomic resolution. Based on hundreds of thousand ligand-binding events, we find that cannabinoids bind to the transmembrane domain of the receptor at both intrasubunit and intersubunit sites. For THC, the intrasubunit binding mode predicted in simulation is in excellent agreement with recent cryo-EM structures, while intersubunit binding recapitulates in full previous mutagenesis experiments. Intriguingly, AEA is predicted to bind at the same intersubunit site despite the strikingly different chemistry. Statistical analyses of the receptor-ligand interactions highlight potentially relevant residues for GlyR potentiation, offering experimentally testable predictions. The predictions for AEA are validated by electrophysiology recordings of rationally designed mutants. The results highlight the existence of multiple cannabinoid-binding sites for the allosteric regulation of GlyR and put forward an effective strategy for the identification and structural characterization of allosteric sites in transmembrane proteins.

biophysics↗