Carlo Guardiani

Carlo Guardiani
Università degli studi di Cagliari | UNICA · Department of Physics

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51
Publications
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419
Citations

Publications

Publications (51)
Article
Full-text available
Ion channels are fundamental biological devices that act as gates in order to ensure selective ion transport across cellular membranes; their operation constitutes the molecular mechanism through which basic biological functions, such as nerve signal transmission and muscle contraction, are carried out. Here, we review recent results in the field o...
Article
Full-text available
The elusive activation/deactivation mechanism of hERG is investigated, a voltage-gated potassium channel involved in severe inherited and drug-induced cardiac channelopathies, including the Long QT Syndrome. Firstly, the available structural data are integrated by providing a homology model for the closed state of the channel. Secondly, molecular d...
Article
Full-text available
The KCNA2 gene encodes the K v 1.2 channel, a mammalian Shaker-like voltage-gated K ⁺ channel, whose defections are linked to neuronal deficiency and childhood epilepsy. Despite the important role in the kinetic behavior of the channel, the inactivation remained hereby elusive. Here, we studied the K v 1.2 inactivation via a combined simulation/net...
Article
Full-text available
CRAC channel is ubiquitous and its importance in the regulation of the immune system is testified by the severe immunodeficiencies caused by its mutations. In this work we took advantage of the availability of open and closed structures of this channel to run for the first time simulations of the whole gating process reaching the relevant time-scal...
Article
Full-text available
In order to permeate a nanopore, an ion must overcome a dehydration energy barrier caused by the redistribution of surrounding water molecules. The redistribution is inhomogeneous, anisotropic and strongly position-dependent, resulting in complex patterns that are routinely observed in molecular dynamics simulations. Here, we study the physical ori...
Article
Full-text available
Most analytic theories describing electrostatically driven ion transport through water-filled nanopores assume that the corresponding permeation barriers are bias-independent. While this assumption may hold for sufficiently wide pores under infinitely small bias, transport through subnanometer pores under finite bias is difficult to interpret analy...
Article
Full-text available
Biological ion channels are fundamental to maintaining life. In this manuscript we apply our recently developed statistical and linear response theory to investigate Na+ conduction through the prokaryotic Na+ channel NaChBac. This work is extended theoretically by the derivation of ionic conductivity and current in an electrochemical gradient, thus...
Article
Full-text available
Voltage-gated sodium channels (NaVs) play fundamental roles in eukaryotes, but their exceptional size hinders their structural resolution. Bacterial NaVs are simplified homologues of their eukaryotic counterparts, but their use as models of eukaryotic Na+ channels is limited by their homotetrameric structure at odds with the asymmetric Selectivity...
Preprint
Full-text available
In order to permeate a nanopore, an ion must overcome a dehydration energy barrier caused by the redistribution of surrounding water molecules. The redistribution is inhomogeneous, anisotropic and strongly position-dependent, resulting in complex patterns that are routinely observed in molecular dynamics simulations. We now address the questions of...
Article
Full-text available
Selective permeation through graphene nanopores is attracting increasing interest as an efficient and cost-effective technique for water desalination and purification. In this work, using umbrella sampling and molecular dynamics simulations with constant electric field, we analyze the influence of pore charge on potassium and chloride ion permeatio...
Article
Full-text available
A key driving force for ion channel selectivity is represented by the negative charge of the Selectivity Filter carried by aspartate (D) and glutamate (E) residues. However, the structural effects and specific properties of D and E residues have not been extensively studied. In order to investigate this issue we studied the mutants of NaChBac chann...
Article
The yeast Saccharomyces cerevisiae genome is endowed with two distinct isoforms of Voltage-Dependent Anion Channel (VDAC). The isoform yVDAC2 is currently understudied with respect to the best known yVDAC1. Yet, since the discovery, the function of yVDAC2 was unclear, leading to the hypothesis that it might be devoid of a channel function. In this...
Article
Full-text available
Ion channel selectivity is essential for their function, yet the molecular basis of a channel's ability to select between ions is still rather controversial. In this work, using a combination of molecular dynamics simulations and electrophysiological current measurements we analyze the ability of the NaChBac channel to discriminate between calcium...
Article
NaChBac was the first discovered sodium voltage dependent channel, yet computational studies are still limited due to the lack of a crystal structure. In this work a pore-only construct built using the NavMs template was investigated using unbiased Molecular Dynamics and Metadynamics. The Potential of Mean Force (PMF) from the unbiased run features...
Conference Paper
The human VDAC channel exists in three isoforms characterized by high sequence homology and structural similarity. Yet the function and mode of action of hVDAC3 are still elusive. The presence of six surface cysteines exposed to the oxidizing environment of the mitochondrial inter-membrane space suggests the possible establishment of intramolecular...
Article
The human VDAC channel exists in three isoforms characterized by high sequence homology and structural similarity. Yet the function and mode of action of hVDAC3 is still elusive. The presence of six surface cysteines exposed to the oxidizing environment of the mitochondrial inter-membrane space suggests the possible establishement of intramolecular...
Article
Full-text available
Voltage-Dependent Anion selective Channels (VDAC) are pore-forming mitochondrial outer membrane proteins. In mammals VDAC3, the least characterized isoform, presents a set of cysteines predicted to be exposed toward the intermembrane space. We find that cysteines in VDAC3 can stay in different oxidation states. This was preliminary observed when, i...
Article
The voltage-dependent anion channel (VDAC) is the main mitochondrial porin allowing the exchange of ions and metabolites between the cytosol and the mitochondrion. In addition, VDAC was found to actively interact with proteins playing a fundamental role in the regulation of apoptosis and being of central interest in cancer research. VDAC is a large...
Article
Small-molecule inhibitors of Tumor Necrosis Factor α Converting Enzyme (TACE) are a promising therapeutic tool for Rheumatoid Arthritis, Multiple Sclerosis and other autoimmune diseases. Here we report on an extensive chemical-physical analysis of the media effects in modulating the conformational landscape of MBET306, the common scaffold and a syn...
Data
A paper entitled “Media effects in modulating the Zinc(II) binding affinity of a model compound for Tumor Necrosis factor converting enzyme inhibition” was originally submitted to the Journal of Physical Chemistry B (JPCB) on the 22nd August 2014. On 13-th of October 2015 the article was reviewed by three referees and rejected “on the basis of [the...
Data
Response to the referees of "Chemical-physical analysis of a tartrate model compound for TACE inhibition"
Data
Response to the referees of "The conformational landscape of tartrate-based inhibitors of the TACE enzyme as revealed by Hamiltonian Replica Exchange simulation."
Data
Second response to the referees of "The conformational landscape of tartrate-based inhibitors of the TACE enzyme as revealed by Hamiltonian Replica Exchange simulation."
Article
The VDAC (Voltage Dependent Anion selective Channel) family of proteins is composed of three evolutionary related isoforms in vertebrates [1-2]. Despite the sequence similarity, the functional data existing nowadays point to different functions for them. The isoforms are expressed at different levels [3], and show a different ability to complement...
Article
We introduce an effective technique for the calculation of the binding free energy in drug-receptor systems using nonequilibrium molecular dynamics and application of the Jarzynski theorem. In essence, this novel methodology constitutes the nonequilibrium adaptation of an ancient free energy perturbation technique called Double Annihilation Method,...
Article
Full-text available
Recent single-molecule force spectroscopy experiments on the Maltose Binding Proteins (MBPs) identified four stable structural units, termed unfoldons, that resist mechanical stress and determine the intermediates of the unfolding pathway. In this work, we analyze the topological origin and the dynamical role of the unfoldons using an integrated ap...
Article
Full-text available
There is now a certain consensus that transcription factors (TFs) reach their target sites, where they regulate gene transcription, via a mechanism dubbed facilitated diffusion (FD). In FD, the TF cycles between events of 3D diffusion in solution (jumps), 1D diffusion along DNA (sliding), and small jumps (hopping), achieving association rates highe...
Article
Full-text available
We have synthesized and done an extensive chemical-physical analysis of the behavior of a new compound, named MBET306, a synthetic precursor of the recently discovered tartrate-based inhibitors of the protein Tumor Necrosis factor-α Converting Enzyme (TACE). Experimental and theoretical data have shown that in water solution MBET306 is overwhelming...
Article
Full-text available
Proliferating cell nuclear antigen and the checkpoint clamp Rad9-Rad1-Hus1 topologically encircle DNA and act as mobile platforms in the recruitment of proteins involved in DNA damage response and cell cycle regulation. To fulfill these vital cellular functions, both clamps need to be opened and loaded onto DNA by a clamp loader complex—a process,...
Article
Full-text available
The inhibitors of the Tumor Necrosis Factor-α Converting Enzyme represent promising tools for the treatment of Rheumatoid Arthritis, Multiple Sclerosis and other autoimmune diseases. In this work, using Hamiltonian Replica Exchange Molecular Dynamics simulations and atomistic force field we perform an accurate structural characterization of a group...
Article
Full-text available
Synthetic N-glycosylated CSF114(Glc) and related peptides were proved to be able to recognize specific and high-affinity autoantibodies circulating in blood of relapsing-remitting multiple sclerosis (MS) patients and correlating with disease activity. The effect of these peptides has been linked to the β-turn structure around the minimal epitope As...
Article
Coarse-grained models are experiencing a renewed interest as they grant access to biologically relevant length and time-scales, they allow to single out molecular driving forces from a plethora of biochemical details. Topological models, discussed in the first part of the chapter, are based on the minimal frustration principle that justifies the st...
Article
Full-text available
Histone H4 undergoes extensive post-translational modifications (PTMs) at its N-terminal tail. Many of these PTMs profoundly affect the on and off status of gene transcription. The molecular mechanism by which histone PTMs modulate genetic and epigenetic processes is not fully understood. In particular, how a PTM mark affects the presence and level...
Article
Full-text available
One of the most important targets in the autoimmune attack in experimental autoimmune encephalomyielitis is the myelin oligodendrocyte glycoprotein (MOG). The complex with demyelinating 8-18C5 antibody was recently resolved by X-ray crystallography, showing a remarkable adhesion of the 101-108 MOG subsequence to the heavy chain of the autoantibody....
Article
Full-text available
The theoretical prediction of protein structures has become a field of increasing importance in both biology and physics. Reliable prediction methods in fact, would spare time consuming experimental X-ray and NMR techniques and they would represent a challenge for computational protein modeling as well. The well known limitations of all-atom models...
Article
Multiple Sclerosis (MS) is a highly invalidating autoimmune disease of the central nervous system, leading to progressive paralysis and, sometimes, to premature death. One of the potential targets of the autoimmune reaction is the myelin protein MOG (Myelin Oligodendrocyte Glycoprotein). Since the 101-108 fragment of MOG plays a key role in the int...
Article
Full-text available
The folding properties of wild type and mutants of domain C5 from cardiac myosin binding protein C have been investigated via molecular dynamics simulations within the framework of a native-centric and coarse-grained model. The relevance of a mutation has been assessed through the shift in the unfolding temperature, the change in the unfolding rate...
Article
The impact of three mutations of domain C5 from myosin binding protein C, correlated to Familial Hypertrophic Cardiomyopathy, has been assessed through molecular dynamics simulations based on a native centric protein modeling. The severity of the phenotype correlates with the shift in unfolding temperature determined by the mutations. A contact pro...
Article
Three mutations of domain C5 of Myosin Binding Protein C are involved in Familial Hypertrophic Cardiomyopathy. We assess their impact through Molecular Dynamics simulations within the framework of a native-centric coarse-grained model. We characterize the clinical relevance of a mutation by: the extent of temperature shift it induces in the unfoldi...
Article
Thermal folding molecular dynamics simulations of the domain C5 of Myosin binding protein C were performed using a native-centric model to study the role of three mutations related to Familial Hypertrophic Cardiomyopathy. Mutation of Asn755 causes the largest shift of the folding temperature, and the residue is located in the CFGA' beta-sheet featu...
Article
Full-text available
We present an extremely simplified model of multiple-domain polymer stretching in an atomic force microscopy experiment. We portray each module as a binary set of contacts and decompose the system energy into a harmonic term (the cantilever) and long-range interaction terms inside each domain. Exact equilibrium computations and Monte Carlo simulati...
Article
The WW domain of the human Pin1 protein for its simple topology and large amount of experimental data is an ideal candidate to assess theoretical approaches to protein folding. The purpose of this work is to compare the reliability of the chemically based Sorenson/Head-Gordon (SHG) model and a standard native centric model in reproducing, through m...
Conference Paper
Full-text available
A probabilistic cellular automaton is developed to study the combined effect of competition and assortativity on the speciation process in the absence of geographical barriers. The model is studied in the case of long-range coupling. A simulated annealing technique was used in order to find the stationary distribution in reasonably short simulatio...
Article
We study the evolution of recombination using a microscopic model developed within the frame of the theory of quantitative traits. Two components of fitness are considered: a static one that describes adaptation to environmental factors not related to the population itself, and a dynamic one that accounts for interactions between organisms e.g. com...
Article
A microscopic model is developed, within the frame of the theory of quantitative traits, to study both numerically and analytically the combined effect of competition and assortativity on the sympatric speciation process, i.e. speciation in the absence of geographical barriers. Two components of fitness are considered: a static one that describes a...
Article
Full-text available
The present paper is the second of a series in which we perform molecular dynamics simulations on the WW domain of Pin1 protein. The aim of the work is the reconstruction of the folding/unfolding pathway with a special interest for the kinetic bottlenecks. In the rst paper of the series we showed that unfolding simulations using the Sorenson/Head-G...
Article
Full-text available
The availability of a large amount of experimental data makes the Pin1 WW domain an ideal benchmark to test computational methods. The purpose of the present work is to identify the kinetic bottlenecks of the folding/unfolding pathway through Molecular Dynamics simulations. In this paper, the rst of the series, we use the Sorenson/Head-Gordon model...