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Dynamical interplay between the human high-affinity copper transporter hCtr1 and its cognate metal ion
Gulshan Walke , Jana Aupič, Hadeel Kashoua , Pavel Janoš, Shelly Meron , Yulia Shenberger , Zena Qasem , Lada Gevorkyan-Airapetov , Alessandra Magistrato, Sharon Ruthstein , 2022, izvirni znanstveni članek

Opis: Abnormal cellular copper levels have been clearly implicated in genetic diseases, cancer, and neurodegeneration. Ctr1, a high-affinity copper transporter, is a homotrimeric integral membrane protein that provides the main route for cellular copper uptake. Together with a sophisticated copper transport system, Ctr1 regulates Cu(I) metabolism in eukaryotes. Despite its pivotal role in normal cell function, the molecular mechanism of copper uptake and transport via Ctr1 remains elusive. In this study, electron paramagnetic resonance (EPR), UV-visible spectroscopy, and all-atom simulations were employed to explore Cu(I) binding to full-length human Ctr1 (hCtr1), thereby elucidating how metal binding at multiple distinct sites affects the hCtr1 conformational dynamics. We demonstrate that each hCtr1 monomer binds up to five Cu(I) ions and that progressive Cu(I) binding triggers a marked structural rearrangement in the hCtr1 C-terminal region. The observed Cu(I)-induced conformational remodeling suggests that the C-terminal region may play a dual role, serving both as a channel gate and as a shuttle mediating the delivery of copper ions from the extracellular hCtr1 selectivity filter to intracellular metallochaperones. Our findings thus contribute to a more complete understanding of the mechanism of hCtr1-mediated Cu(I) uptake and provide a conceptual basis for developing mechanism-based therapeutics for treating pathological conditions linked to de-regulated copper metabolism.
Ključne besede: ctr1, copper, epr, molecular dynamics
Objavljeno v RUNG: 15.09.2022; Ogledov: 856; Prenosov: 0
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The conformational plasticity of the selectivity filter methionines controls the in-cell Cu(I) uptake through the CTR1 transporter
Pavel Janoš, Jana Aupič, Sharon Ruthstein , Alessandra Magistrato, 2022, izvirni znanstveni članek

Opis: Copper is a trace element vital to many cellular functions. Yet its abnormal levels are toxic to cells, provoking a variety of severe diseases. The high affinity copper transporter 1 (CTR1), being the main in-cell copper [Cu(I)] entry route, tightly regulates its cellular uptake via a still elusive mechanism. Here, all-atoms simulations unlock the molecular terms of Cu(I) transport in eukaryotes disclosing that the two methionine (Met) triads, forming the selectivity filter, play an unprecedented dual role both enabling selective Cu(I) transport and regulating its uptake rate thanks to an intimate coupling between the conformational plasticity of their bulky side chains and the number of bound Cu(I) ions. Namely, the Met residues act as a gate reducing the Cu(I) import rate when two ions simultaneously bind to CTR1. This may represent an elegant autoregulatory mechanism through which CTR1 protects the cells from excessively high, and hence toxic, in-cell Cu(I) levels. Overall, our outcomes resolve fundamental questions in CTR1 biology and open new windows of opportunity to tackle diseases associated with an imbalanced copper uptake.
Ključne besede: copper, membrane transporter, molecular dynamics, QM/MM, free energy
Objavljeno v RUNG: 15.09.2022; Ogledov: 930; Prenosov: 0
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Probing the folding of hen lyzozyme through molecular dynamics simulations
Bariş Kalfa, 2022, raz. nal. na višji ali visoki šoli

Ključne besede: molecular dynamics simulations, proteins, folding process, unfolding process, hen egg-white lysozyme
Objavljeno v RUNG: 25.08.2022; Ogledov: 795; Prenosov: 0
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The dissociation constant of water at extreme conditions: a molecular dynamics study
Rabi Khanal, 2012, diplomsko delo

Ključne besede: water, molecular dynamics, pK, dissociation, Bluemoon approach
Objavljeno v RUNG: 21.03.2019; Ogledov: 3158; Prenosov: 1
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Nanobodies: towards rational design of immune-reagents
Ario De Marco, 2017, objavljeni povzetek znanstvenega prispevka na konferenci (vabljeno predavanje)

Opis: Antibodies are irreplaceable reagents in both research and clinical practice. Despite their relevance, the structural complexity of conventional mono- and polyclonal antibodies (IgG) has always been a limit for their engineering towards reagents optimized for specific applications, such as in vivo diagnostics and therapy. Furthermore, their isolation is time consuming, their production expensive, and their functionalization results often in heterogeneous macromolecule populations. These drawbacks promoted the search for both innovative antibody isolation strategies and alternative scaffolds. In vitro panning of pre-immune collections of recombinant antibody fragments allows for the simple and fast recovery of binders. Since they did not undergo somatic maturation, their affinity for targets can be insufficient but on the other hand they can be rapidly mutated by standard molecular biology techniques to generate second-generation antibodies among which to identify clones with improved characteristics. Both stochastic and rational methods have been proposed for the optimization process. Random mutagenesis followed by panning at stringent conditions has been successful used to select binders with improved physical characteristics. Rational methods try to identify in silico key residues involved in the regulation of specific antibody features, such as stability or binding affinity. The accuracy of these methods usually depends on the calculation resources. In this perspective, smaller molecules can be analyzed “better” than larger because of their restricted number of residues. Nanobodies small dimensions have been long appreciated since enable better tissue penetration, shorter clearance time, higher yields. Now it becomes evident that this characteristic makes them also optimal objects for modeling.
Ključne besede: recombinant antibody modeling, nanobody engineering, molecular dynamics and docking
Objavljeno v RUNG: 21.03.2018; Ogledov: 4107; Prenosov: 0
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Distance-based configurational entropy of proteins from molecular dynamics simulations
Federico Fogolari, Alessandra Corazza, Sara Fortuna, Miguel Angel Soler, Bryan VanSchouwen, Giorgia Brancolini, Stefano Corni, Giuseppe Melacini, Gennaro Esposito, 2015, izvirni znanstveni članek

Opis: Estimation of configurational entropy from molecular dynamics trajectories is a difficult task which is often performed using quasi-harmonic or histogram analysis. An entirely different approach, proposed recently, estimates local density distribution around each conformational sample by measuring the distance from its nearest neighbors. In this work we show this theoretically well grounded the method can be easily applied to estimate the entropy from conformational sampling. We consider a set of systems that are representative of important biomolecular processes. In particular: reference entropies for amino acids in unfolded proteins are obtained from a database of residues not participating in secondary structure elements; the conformational entropy of folding of β2-microglobulin is computed from molecular dynamics simulations using reference entropies for the unfolded state; backbone conformational entropy is computed from molecular dynamics simulations of four different states of the EPAC protein and compared with order parameters (often used as a measure of entropy); the conformational and rototranslational entropy of binding is computed from simulations of 20 tripeptides bound to the peptide binding protein OppA and of β2-microglobulin bound to a citrate coated gold surface. This work shows the potential of the method in the most representative biological processes involving proteins, and provides a valuable alternative, principally in the shown cases, where other approaches are problematic.
Ključne besede: entropy, protein, molecular dynamics, simulations, MD
Objavljeno v RUNG: 12.10.2016; Ogledov: 3929; Prenosov: 220
.pdf Celotno besedilo (2,40 MB)

Accurate estimation of the entropy of rotation-translation probability distributions
Federico Fogolari, Cedrix Jurgal Dongmo Foumthuim, Sara Fortuna, Miguel Angel Soler, Alessandra Corazza, Gennaro Esposito, 2016, izvirni znanstveni članek

Opis: The estimation of rotational and translational entropies in the context of ligand binding has been the subject of long-time investigations. The high dimensionality (six) of the problem and the limited amount of sampling often prevent the required resolution to provide accurate estimates by the histogram method. Recently, the nearest-neighbor distance method has been applied to the problem, but the solutions provided either address rotation and translation separately, therefore lacking correlations, or use a heuristic approach. Here we address rotational–translational entropy estimation in the context of nearest-neighbor-based entropy estimation, solve the problem numerically, and provide an exact and an approximate method to estimate the full rotational–translational entropy.
Ključne besede: entropy, probability distribution, molecular dynamics, nearest-neighbor
Objavljeno v RUNG: 11.10.2016; Ogledov: 4022; Prenosov: 0
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Molecular dynamics simulations and docking enable to explore the biophysical factors controlling the yields of engineered nanobodies
Miguel Soler, Ario de Marco, Sara Fortuna, 2016, izvirni znanstveni članek

Opis: Nanobodies (VHHs) have proved to be valuable substitutes of conventional antibodies for molecular recognition. Their small size represents a precious advantage for rational mutagenesis based on modelling. Here we address the problem of predicting how Camelidae nanobody sequences can tolerate mutations by developing a simulation protocol based on all-atom molecular dynamics and wholemolecule docking. The method was tested on two sets of nanobodies characterized experimentally for their biophysical features. One set contained point mutations introduced to humanize a wild type sequence, in the second the CDRs were swapped between single-domain frameworks with Camelidae and human hallmarks. The method resulted in accurate scoring approaches to predict experimental yields and enabled to identify the structural modifications induced by mutations. This work is a promising tool for the in silico development of single-domain antibodies and opens the opportunity to customize single functional domains of larger macromolecules
Ključne besede: nanobodies, molecular dynamics, modeling, antibody solubility
Objavljeno v RUNG: 11.10.2016; Ogledov: 4371; Prenosov: 243
.pdf Celotno besedilo (1,95 MB)

Computational design of customised nanobodies for biotechnological applications
Miguel Soler, Ario de Marco, Sara Fortuna, 2016, prispevek na konferenci brez natisa

Opis: In silico modeling to improve the biophysical characteristics of recombinant single-domain antibodies
Ključne besede: nanobodies, modeling, protein stability, antibody humanization, molecular dynamics
Objavljeno v RUNG: 26.04.2016; Ogledov: 4271; Prenosov: 0
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