1,721,072 research outputs found
Mechanism of proteolysis of anthrax lethal factor. An ab initio and hybrid QM/MM molecular dynamics study
No full textThe disease anthrax is caused by lethal factor (LF), an enzyme component of the toxin produced by the bacterium Bacillus Anthracis. Our studies are devoted to shed light on the binding and proteolytic mechanism of MAPKK kinase family promoted by anthrax lethal factor. At first, based on the X-ray structure of LF we have provided an understanding of the structural determinants and the hydrogen bond network that surrounds the LF active site, using static and dynamic density functional (DFT) calculations. Subsequently, classical molecular dynamics simulations have been performed on the entire protein structure and the solvent waters in order to clarify the binding and the specific substrate-protein interactions of MAPKK to the active site of LF. Finally, hybrid quantum/classical (QM/MM) molecular dynamics simulations have been performed on the entire protein structure and the solvent in order to understand the exact mechanism by which LF cleaves the NH2-termini of the MAPK-kinase family
Azole-bridged diplatinum anticancer drugs: Escaping repair mechanism and avoiding cross-resistance by modulating DNA-flexibility
No full textINOR 531-Binding of novel azole-bridged dinuclear platinum(II) anticancer drugs to DNA: Insights from QM/MM molecular dynamics simulations
No full textDirect in silico visualization of ligands channelling through proteins: The next-generation frontier of computational biology
No full textInfluence of the membrane lipophilic environment on the structure and on the substrate access/egress routes of the human aromatase enzyme. A computational study
No full textHuman aromatase (HA), an enzyme located on the membrane of the endoplasmatic reticulum, is of crucial biological importance in the biosynthesis of estrogens. High levels of estrogens are related with important pathologies, conferring to HA a key role as a pharmacological target. In this study we provide, for the first time, an atomistic model of HA embedded on a membrane model to understand the influence of the membrane lipophilic environment on the structural and dynamical properties of HA and on the access/egress pathways of the substrate (androstenedione, ASD) and of the oxygen molecule (involved in the enzymatic process) into/from the HA active site. To this end we used several computational techniques such as force field-based molecular dynamics (MD) simulations, Random Expulsion MD, Steered MD, and Implicit Ligand Sampling. Our results show that the membrane anchoring does not markedly affect the structural properties and the flexibility of the protein, but they clearly point out that the membrane has a marked effect on the access/egress routes of the reactants, stabilizing the formation of different channels for both ASD and O-2 with respect to those observed in pure water solution. Due to the importance of HA in medicine and since access/egress channels may influence its substrate selectivity, a detailed understanding of the role of the membrane in shaping these channels may be of valuable help in drug design
First-Principles Modeling of Biological Systems and Structure-Based Drug-Design
No full textMolecular modeling techniques play a relevant role in drug design providing detailed information at atomistic level on the structural, dynamical, mechanistic and electronic properties of biological systems involved in diseases’ onset, integrating and supporting commonly used experimental approaches. These information are often not accessible to the experimental techniques taken singularly, but are of crucial importance for drug design. Due to the enormous increase of the computer power in the last decades, quantum mechanical (QM) or first-principles-based methods have become often used to address biological issues of pharmaceutical relevance, providing relevant information for drug design. Due to their complexity and their size biological systems are often investigated by means of a mixed quantum-classical (QM/MM) approach, which treats at an accurate QM level a limited chemically relevant portion of the system and at the molecular mechanics (MM) level the remaining of the biomolecule and its environment. This method provides a good compromise between computational cost and accuracy, allowing to characterize the properties of the biological system and the (free) energy landscape of the process in study with the accuracy of a QM description. In this review, after a brief introduction of QM and QM/MM methods, we will discuss few representative examples, taken from our work, of the application of these methods in the study of metallo-enzymes of pharmaceutical interest, of metal-containing anticancer drugs targeting the DNA as well as of neurodegenerative diseases. The information obtained from these studies may provide the basis for a rationale structure-based drug design of new and more efficient inhibitors or drugs
The Structural Role of Mg2+ Ions in a Class I RNA Polymerase Ribozyme. A Molecular Simulation Study
No full textAccording to the RNA world hypothesis, self-replicating ribozymes, storing the genetic information and being able to perform catalysis, were the constituents of the first living organisms. In particular, RNA polymerase ribozymes, similar to current proteinaceous enzymatic polymerases, may have been able to promote the synthesis of RNA strands in a primitive world. Polymerase catalysis is usually assisted by Mg2+ ions, but it is not always trivial to find out experimentally the number of Mg2+ ions placed in the active site as well as the identity and the number of their coordination ligands. Here, we addressed this issue in an artificial class I ligase ribozyme. On the basis of a recently solved crystal structure, we constructed computational models of reactant and product states of this ribozyme, considering monometallic and bimetallic species. Our models were relaxed by force field based molecular dynamics (MD) simulations and mixed quantum-classical (QM/MM) MD. The structural and dynamical properties of these models were consistent with experimental data and were validated by a comparison with the catalytic sites of proteinaceous DNA and RNA polymerases. Consistently with enzymatic polymerases, our results suggest that class I RNA ligases most probably contain two magnesium ions in the active site and they may, therefore, catalyze the junction of two RNA strands via "a two Mg2+ ions" mechanism
Detecting DNA mismatches with metallo-insertors: A molecular simulation study
Full text linkMolecules that selectively recognize DNA mismatches (MMs) play a key role as nucleic acids probes and as chemotherapeutic agents. Metallo-insertors bind to the minor groove (mG) of double strand (ds) DNA, expelling the mismatched base pairs and acting as their π-stacking replacement. In contrast, metallo-intercalators bind to the major groove (MG) of ds DNA and π-stack to adjacent base pairs. In this study we focused on structural and energetic properties of Δ−[Rh(bpy)2(chrysi)]3+ (1), Δ−[Ru(bpy)2(ddpz)]2+ (2), and Δ-[Ru(bpy)2(eilatin)]2+ (3) as prototypical examples of metallo-insertors and intercalators. For all molecules we characterized both insertion and intercalation into a DNA dodecamer via force field based molecular dynamics (MD) and hybrid quantum-classical (QM/MM) MD simulations. A structural analysis of the 1–3/DNA noncovalent adducts reveals that the insertion provokes an untwist of the DNA, an opening of the mG and of the phosphate backbone in proximity of the mismatch, while the intercalation induces smaller changes of these structural parameters. This behavior appears to be correlated with the size of the inserting/intercalating ligand in proximity of the metal coordination site. Moreover, our simulations show that the different selectivity of 1 toward distinct MM types may be correlated with the thermodynamic stability of the MMs in the free DNA and with that of the corresponding insertion adduct. Understanding the factors which tune a specific insertion is of crucial importance for designing specific luminescent probes that selectively recognize MMs, as well as for developing more effective anticancer drugs active in MM repair of deficient cells lines
QM/MM Molecular Dynamics Studies of Metal Binding Proteins
Full text linkMixed quantum-classical (quantum mechanical/molecular mechanical (QM/MM)) simulations have strongly contributed to providing insights into the understanding of several structural and mechanistic aspects of biological molecules. They played a particularly important role in metal binding proteins, where the electronic effects of transition metals have to be explicitly taken into account for the correct representation of the underlying biochemical process. In this review, after a brief description of the basic concepts of the QM/MM method, we provide an overview of its capabilities using selected examples taken from our work. Specifically, we will focus on heme peroxidases, metallo-β-lactamases, α-synuclein and ligase ribozymes to show how this approach is capable of describing the catalytic and/or structural role played by transition (Fe, Zn or Cu) and main group (Mg) metals. Applications will reveal how metal ions influence the formation and reduction of high redox intermediates in catalytic cycles and enhance drug metabolism, amyloidogenic aggregate formation and nucleic acid synthesis. In turn, it will become manifest that the protein frame directs and modulates the properties and reactivity of the metal ions
The molecular mechanism of secondary sodium symporters elucidated through the lens of the computational microscope
Full text linkTransport of molecules across cellular membranes is a key biological process for normal cell function. As such, secondary active transporters exploit electrochemical ion gradients to carry out fundamental processes, i.e. nutrients uptake, ion regulation, neurotransmission, and substrate extrusion. Despite their modest sequence similarity, several Na+ symporters share the same fold of LeuT (leucine transporter), a prokaryotic member of the neurotransmitter-sodium symporter family, pinpointing to a common structural/functional mechanism of transport. This is associated with specific conformational transitions occurring along a so-called alternating access mechanism. Thanks to recent advances in computer simulation techniques and the ever-increasing computational power that has become available in the last decade, molecular dynamics (MD) simulations have been largely employed to provide atomistic insights into mechanistic, kinetic, and thermodynamic aspects of this family of transporters. Here we report a detailed overview of selected Na+-symporters belonging to the LeuT-fold superfamily for which different aspects of the transport mechanism have been addressed using both experimental and computational studies. The aim of this review is to describe current state-of-the-art knowledge on the mechanism of these transporters showing how molecular simulations have contributed to elucidate mechanistic aspects and can provide nowadays a spatial and temporal resolution, allowing the interpretation of experimental findings, complementing biophysical methods, and filling the gaps in fragmentary experimental information
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