Biology subjects

Aureli, S.

Publications and source records attributed to Aureli, S..

3 recordsLinked to original sources

bioRxiv2023

OneOPES, a combined enhanced sampling method to rule them all

Enhanced sampling techniques have revolutionised molecular dynamics (MD) simulations, enabling the study of rare events and the calculation of free energy differences in complex systems. One of the main families of enhanced sampling techniques uses physical degrees of freedom called collective variables (CVs) to accelerate a systems dynamics and recover the original systems statistics. However, encoding all the relevant degrees of freedom in a limited number of CVs is challenging, particularly in large biophysical systems. Another category of techniques, such as parallel tempering, simulates multiple replicas of the system in parallel, with-out requiring CVs. However, these methods may explore less relevant high-energy portions of the phase space and become computationally expensive for large systems. To overcome the limitations of both approaches, we propose a replica exchange method called OneOPES that combines the power of multi-replica simulations and CV-based enhanced sampling. This method efficiently accelerates the phase space sampling without the need for ideal CVs, extensive parameters fine tuning nor the use of a large number of replicas, as demonstrated by its successful applications to protein-ligand binding and protein folding benchmark systems. Our approach shows promise as a new direction in the development of enhanced sampling techniques for molecular dynamics simulations, providing an efficient and robust framework for the study of complex and unexplored problems. Table of Content Graphic O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=104 SRC="FIGDIR/small/531337v2_ufig1.gif" ALT="Figure 1"> View larger version (24K): org.highwire.dtl.DTLVardef@88b5ceorg.highwire.dtl.DTLVardef@15817deorg.highwire.dtl.DTLVardef@8721bforg.highwire.dtl.DTLVardef@1b8b314_HPS_FORMAT_FIGEXP M_FIG C_FIG

biophysics↗

bioRxiv2023

Conformational plasticity and allosteric communication networks govern Shelterin protein TPP1 binding to human telomerase

The molecular binding interaction between the Shelterin complex protein TPP1 and human telomerase enzyme (TERT) triggers the telomerase maintenance mechanism that marks cell lifespan. The TPP1s structural element deputed to bind TERT is the OB-domain, which is able to interact with TERTs hTEN (TPP1 binding telomerase domain) through the TEL-patch, a group of amino acids whose mutations provoke harsh pathologies. Indeed, aberrations in the formation of TPP1-TERT het-erodimer can lead to severe diseases like Hoyeraal-Hreidarsson syndrome (HHS), whose patients are affected by short telomeres and extremely poor life expectancy. In the present study, we provide a thorough characterization of the structural properties of the TPP1s OB-domain by combining data coming from microsecond-long molecular dynamics calculations, time-series analyses, and graph-based networks. Our results show that the conformational plasticity of the TPP1s TEL-patch region is influenced by a network of long-range amino acid communications, needed for the proper TPP1-hTEN binding. Furthermore, we reveal that in the Glu169{Delta} and Lys170{Delta} TPP1 variants, responsible for HHS, the plasticity of the TEL-patch region is reduced, affecting the correct binding to hTEN and in turn the telomere processivity, which eventually leads to accelerated ageing of affected cells. Our study provides an unprecedented structural basis for the design of TPP1-targeting ligands with therapeutic potential against cancer and telomerase deficiency diseases.

biochemistry↗

bioRxiv2022

Subcellular location defines GPCR signal transduction

G protein-coupled receptors in intracellular organelles can be activated in response to membrane permeant ligands, which contributes to the diversity and specificity of agonist action. The opioid receptors (ORs) provide a striking example, where opioid drugs activate ORs in the Golgi apparatus within seconds of drug addition. Till date, our knowledge on the signaling of intracellular GPCRs remains incomplete and it is unknown if the downstream effects triggered by ORs in plasma membrane and Golgi apparatus differ. To address this gap, we first assess the recruitment of signal transducers to ORs in both compartments. We find that Golgi-localized ORs couple to Gi/o probes and are phosphorylated by GPCR kinases (GRK2/3), but unlike plasma membrane receptors, do not recruit {beta}-arrestin or a specific G probe. Subsequent molecular dynamics simulations with OR-transducer complexes in model bilayers mimicking plasma membrane or Golgi composition reveal that the lipid environment promotes location selective coupling. Unbiased global analyses then show that OR activation in the plasma membrane and Golgi apparatus has strikingly different downstream effects on transcription and protein phosphorylation. Taken together, the study delineates OR signal transduction with unprecedented spatial resolution and reveals that the subcellular location defines the signaling effect of opioid drugs.

cell biology↗