Marco D'Abramo

Marco D'Abramo
Sapienza University of Rome | la sapienza · Department of Chemistry

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106
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Publications

Publications (106)
Article
Tetrameric hemoglobins (Hbs) are prototypal systems for studies aimed at unveiling basic structure-function relationships as well as investigating the molecular/structural basis of adaptation of living organisms to extreme conditions. However, a chronological analysis of decade-long studies conducted on Hbs is illuminating on the difficulties assoc...
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The effect of the environment on the guanine redox potential is studied by means of a theoretical-computational approach. Our data, in agreement with previous experimental findings, clearly show that the presence of consecutive guanine bases in both single- and double-stranded DNA oligomers lowers their reduction potential. Such an effect is even m...
Article
The experimental absorption measurements in the interval 350-600 nm (Vis), molecular dynamics simulations, quantum-mechanics calculations and an advanced molecular treatment of simulation data are here combined to provide a complete picture of the absorption behavior in the visible portion of the electromagnetic spectrum of the doxorubicin hydrochl...
Article
Hypothesis Self-assembling molecular structures responding to light stimulus are appealing for applications as sensing and drug delivery. Supramolecular nanotubes have a relevant potential in nanotechnology as they can be used to encapsulate different loads like drugs, biological macromolecules, and nano-materials. In addition, they are suitable el...
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We characterize the folding-unfolding thermodynamics of two mutants of the miniprotein Trp-cage by combining extended molecular dynamics simulations and an advanced statistical-mechanical-based approach. From a set of molecular dynamics simulations in an explicit solvent performed along a reference isobar, we evaluated the structural and thermodyna...
Preprint
Theoretical work suggests that collective spatiotemporal behaviour of integral membrane proteins (IMPs) can be modulated by annular lipids sheathing their hydrophobic moiety. Here, we present evidence for this prediction in a natural membrane by investigating the mechanism that maintains steady amount of active isoform of Lck kinase (LckA) by Lck t...
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The machinery involved in cytotoxic T-cell activation requires three main characters: the major histocompatibility complex class I (MHC I) bound to the peptide (p), the T-cell receptor (TCR), and the CD3 complex, a multidimer interfaced with the intracellular side. The pMHC:TCR interaction has been largely studied by means of both experimental and...
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The estimation of the redox potentials of biologically relevant systems by means of theoretical-computational approaches still represents a challenge. In fact, the size of these systems typically does not allow a full quantum-mechanical treatment needed to describe electron loss/gain in such a complex environment, where the redox process takes plac...
Article
Here we present an advanced theoretical-computational approach to model the electronic circular dichroism (CD) spectrum of the smallest chiral amino acid in water solution. Combining quantum-mechanical calculations with molecular dynamics simulations the electronic and magnetic properties of L-alanine (L-Ala) in solution are obtained and compared w...
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Substrate binding to the cytochrome P450 OleP is coupled to a large open-to-closed transition that remodels the active site, minimizing its exposure to the external solvent. When the aglycone substrate binds, a small empty cavity is formed between the I and G helices, the BC loop, and the substrate itself, where solvent molecules accumulate mediati...
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Electroporation is a well-established technique used to stimulate cells, enhancing membrane permeability by inducing reversible membrane pores. In the absence of experimental observation of the dynamics of pore creation, molecular dynamics studies provide the molecular-level evidence that the electric field promotes pore formation. Although single...
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Src kinases play fundamental roles in several crucial cell processes. Their activity is tightly regulated by conformational transitions between the active and the inactive forms, which are carried out by complex protein structural rearrangements. Here, we present an in-depth study of such structural transitions coupling extensive all-atoms molecula...
Article
How to unveil pathway complexity in a crystallization process? In their Research Article (DOI: 10.1002/anie.202101611), Alessandro Sorrenti, Marco D′Abramo, Guillermo Mínguez Espallargas, Josep Puigmartí‐Luis et al. show that harnessing a reaction–diffusion (RD) process within a continuous flow microfluidic device, and in milliseconds timescale, is...
Article
Wie lässt sich die Komplexität von Kristallisationsprozessen aufdecken? In ihrem Forschungsartikel (DOI: 10.1002/ange.202101611 ) zeigen Alessandro Sorrenti, Marco D′Abramo, Guillermo Mínguez Espallargas, Josep Puigmartí‐Luis et al., dass die Anwendung eines Reaktions‐Diffusions(RD)‐Prozesses in einem Mikrofluidikreaktor im Millisekundenbereich der...
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Coordination polymers (CPs), including metal‐organic frameworks (MOFs), are crystalline materials with promising applications in electronics, magnetism, catalysis, and gas storage/separation. However, the mechanisms and pathways underlying their formation remain largely undisclosed. Herein, we demonstrate that diffusion‐controlled mixing of reagent...
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We show that human-made self-assembled materials, such as porous coordination polymers, can follow distinct growth pathways in a given energy landscape in response to a controlled diffusion of reagents. Abstract Coordination polymers (CPs), including metal–organic frameworks (MOFs), are crystalline materials with promising applications in electron...
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Here, we present the theoretical-computational modeling of the oxidation properties of four DNA nucleosides and nucleotides and a set of dinucleotides in solutions. Our estimates of the vertical ionization energies and reduction potentials, close to the corresponding experimental data, show that an accurate calculation of the molecular electronic p...
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GADD45β/MKK7 complex is a non-redundant, cancer cell-restricted survival module downstream of the NF-kB survival pathway, and it has a pathogenically critical role in multiple myeloma, an incurable malignancy of plasma cells. The first-in-class GADD45β/MKK7 inhibitor DTP3 effectively kills MM cells expressing its molecular target, both in vitro and...
Preprint
Full-text available
The machinery involved in cytotoxic T-cell activation requires three main characters such as: the major histocompatibility complex class I (MHC I) bound to the peptide (p), the T-cell receptor (TCR), and the CD3-complex which is a multidimer interfaced with the intracellular side. The pMHC:TCR interaction has been largely studied both in experiment...
Article
In the present study, we apply a computational approach, based on DFT calculations and molecular dynamics simulations, to investigate the catalytic behavior of four supramolecular catalysts active in the cleavage of phosphodiesters. The QM data indicate the operation of a synchronous associative mechanism with limited differences in the structures...
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The major defense system against microbial pathogens in vertebrates is the adaptive immune response and represents an effective mechanism in cancer surveillance. T cells represent an essential component of this complex system. They can recognize myriads of antigens as short peptides (p) originated from the intracellular degradation of foreign prote...
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Here, we present the theoretical–computational modelling of the free energy barrier of the phosphodiester bond cleavage as occurring in the mesophilic variant of endonuclease I-DmoI bound to DNA. Our data, obtained by means of hybrid quantum mechanics/molecular mechanics approach, indicate that the influence of the environment, exerted by the enzym...
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In this work we describe the application of the Zernike formalism to quantitatively characterize the binding pockets of two sets of biologically relevant systems. Such an approach, when applied to molecular dynamics trajectories, is able to pinpoint the subtle differences between very similar molecular regions and their impact on the local propensi...
Article
Here we present a theoretical-computational study of thermodynamics and kinetics of aqueous Trpcage. The combined use of accurate molecular dynamics simulations rigorously reconstructing the proper isobar of the system and...
Article
Biomolecule derivatives are transversally used in nanotechnology. Deciphering their aggregation behavior is a crucial issue for the rational design of functional materials. To this end, it is necessary to build libraries of selectively functionalized analogues and infer general rules. In this work we enrich the highly applicative oriented collectio...
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In this article, we investigated the structural and dynamical evolutionary behaviour of a set of ten thioredoxin proteins as formed by three extant forms and seven resurrected ones in laboratory. Starting from the crystallographic structures, we performed all-atom molecular dynamics simulations and compare the trajectories in terms of structural an...
Article
Using a combined approach based on MS, enzyme digestion and advanced MD studies we have determined the sequential order of formation of the three disulfide bridges of the Cripto-1 CFC domain. The domain has a rare pattern of bridges and is involved in the recognition of several receptors. The bridge formation order is C1-C4, C3-C5, C2-C6, however f...
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The human leukocyte antigen HLA-B27 is a strong risk factor for Ankylosing Spondylitis (AS), an immune-mediated disorder affecting axial skeleton and sacroiliac joints. Additionally, evidence exists sustaining a strong protective role for HLA-B27 in viral infections. These two aspects could stem from common molecular mechanisms. Recently, we have f...
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Here we report the description of the conformational pathways connecting the Lck active and inactive states by means of all-atoms molecular dynamics simulations coupled to an enhancing sampling methodology. By such an approach, we describe the major structural determinants characterizing these large conformational transitions and compare such pathw...
Article
The self-association equilibria of doxorubicin hydrochloride (DX), at high drug and NaCl concentrations, are studied by temperature scan fluorescence spectroscopy, with the support of molecular dynamics (MD) calculations. Even though all anthracyclines show dimerization equilibria, DX only can further associate into long polymeric chains according...
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The dihydroorotase (DHOase) domain of the multifunctional protein carbamoyl-phosphate synthetase 2, aspartate transcarbamoylase, and dihydroorotase (CAD) catalyzes the third step in the de novo biosynthesis of pyrimidine nucleotides in animals. The crystal structure of the DHOase domain of human CAD (huDHOase) revealed that, despite evolutionary di...
Article
Some years ago we developed a theoretical-computational hybrid quantum/classical methodology, the Perturbed Matrix Method (PMM), to be used in conjuction with molecular dynamics simulations for the investigation of chemical processes in complex systems, that proved to be a valuable tool for the simulation of relevant experimental observables, e.g.,...
Article
The theoretical computational modelling of large conformational transitions occurring in biomolecules still represents a challenge. Here we present an accurate “in-silico” description of the activation and deactivation mechanism of human c-Src kinase, a fundamental process regulating several crucial cell functions. Our results clearly show that, ap...
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The high DNA specificity of homing endonucleases makes them a powerful protein scaffold to engineer enzymes for genome manipulation. Understanding their molecular recognition of DNA is an important prerequisite to generate engineered enzymes able to cleave DNA in specific desired genome sites. Protein-DNA recognition studies have been mostly focuse...
Article
Anthracyclines self-assemble in water into dimers. In the presence of sufficiently high salt (NaCl) concentrations, solutions of the antibiotic doxorubicin, but not those of the closely related molecules daunomycin and epirubicin, turn into gels barely compatible with the presence of small oligomers. The use of spectroscopic, scattering, imaging an...
Article
In the context of our research on stimuli-responsive polymers bearing the 2-(hydroxyimino)aldehyde (HIA) group, we explore the photochemical behavior and physico-chemical properties of a number of HIAs. Interpretation of experimental data is supported by quantum mechanical calculations. HIAs are expected to undergo photoisomerization, chelate metal...
Article
Thymidine phosphorylase (TP) is an enzyme that is up-regulated in a wide variety of solid tumors, including breast and colorectal cancers. It is involved in tumor growth and metastasis, for this reason it is one of the key enzyme to be inhibited, in an attempt to prevent tumor proliferation. However, it also plays an active role in cancer treatment...
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I-DmoI, from the hyperthermophilic archaeon Desulfurococcus mobilis, belongs to the LAGLIDADG homing endonuclease protein family. Its members are highly specific enzymes capable of recognizing long DNA target sequences, thus providing potential tools for genome manipulation. Working towards this particular application, many efforts have been made t...
Article
Despite an intense interest and a remarkable number of studies on the subject, the relationships between thermostability and (primary, secondary and tertiary) structure of proteins are still not fully understood. Here, comparing the protein density – defined by the ratio between the residue number and protein excluded volume – for a set of thermoph...
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The conformational behavior of the wild-type Endonucleases I-DmoI and two of its mutants has been studied in presence and in absence of DNA target sequences by means of extended molecular dynamics simulations. Our results show that in absence of DNA, the three protein forms explore a similar essential conformational space, whereas when bound to the...
Article
The hydration structure dynamics of Cu(II) ion is characterized by a combination of classical Molecular Dynamics simulation and X-ray absorption near-edge spectroscopy. Previous experimental data have been analyzed on the basis of five- or six-fold first hydration structure, with a quite well-established equatorial structure. This four-fold equator...
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In this study, we have applied a theoretical–computational methodology, developed in our laboratory and based on molecular dynamics simulations and quantum-chemical calculations, for modelling the kinetics of photoinduced electron-transfer (ET) reaction between two chromophores covalently linked to a peptide in acetonitrile solution. The results, i...
Article
In a previous investigation, cationic liposomes formulated with new 5-FU derivatives, differing for the length of the polyoxyethylenic spacer that links the N3 position of 5-FU to an alkyl chain of 12 carbon atoms, showed a higher cytotoxicity compared to free 5-FU, the cytotoxic effect being directly related to the length of the spacer. To better...
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Homing endonucleases, such as I-DmoI, specifically recognize and cleave long DNA target sequences (~ 20 bp) and are potentially powerful tools for genome manipulation. However, inefficient and off-target DNA cleavage seriously limit specific editing in complex genomes. One approach to overcome these limitations is to unambiguously identify the key...
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In this paper we present a computational approach, based on NVT molecular dynamics trajectories, that allows the direct evaluation of the protein partial molecular volume. The results obtained for five different globular proteins demonstrate the accuracy of this computational procedure in reproducing protein partial molecular volumes, providing qua...
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The Trp53 gene is the most frequently mutated gene in all human cancers. Its protein product p53 is a very powerful transcription factor that can activate different biochemical pathways and affect the regulation of metabolism, senescence, DNA damage response, cell cycle and cell death. The understanding of its function at the molecular level could...
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Homing endonucleases are useful tools for genome modification due to their capability to recognize and cleave specifically large DNA targets. These endonucleases generate a DNA double-strand break that can be repaired by the DNA damage response machinery. The break can be repaired by homologous recombination, an error-free mechanism, or by non-homo...
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Couplings between protein sub-structures are a common property of protein dynamics. Some of these couplings are especially interesting since they relate to function and its regulation. In this article we have studied the case of cavity couplings because cavities can host functional sites, allosteric sites, and are the locus of interactions with the...
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In this study we propose a theoretical-computational method, essentially based on molecular dynamics simulations and quantum-chemical calculations, for modelling the photo-induced charge separation (CS) and the subsequent charge recombination (CR) processes in solution. In particular we have reproduced the low-energy UV-Vis spectra of systems compo...
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Protein kinases work because their flexibility allows to continuously switch from inactive to active form. Despite the large number of structures experimentally determined in such states, the mechanism of their conformational transitions as well as the transition pathways are not easily to capture. In this regard, computational methods can help to...