Influence of temperature on the topological features of inner cavities in cytoglobin

Cytoglobin (Cygb) is a novel member of the globin family in man, but there is no clear evidence about its biological function. Cygb exhibits a highly complex ligand rebinding kinetics, which agrees with the structural plasticity of the inner cavities and tunnels found in the protein matrix. In this work we have examined the effect of temperature on the topological features of Cygb. To this end, the structural and dynamical properties of human Cygb are compared with those determined for the Antarctic fish Chaenocephalus aceratus. The results support a distinct temperature-dependence of the topological features in the two proteins, suggesting different adaptations to cold and warm environments

Influence of temperature on the topological features of inner cavities in cytoglobin

Cytoglobin (Cygb) is a novel member of the globin family in man, but there is no clear evidence about its biological function. Cygb exhibits a highly complex ligand rebinding kinetics, which agrees with the structural plasticity of the inner cavities and tunnels found in the protein matrix. In this work we have examined the effect of temperature on the topological features of Cygb. To this end, the structural and dynamical properties of human Cygb are compared with those determined for the Antarctic fish Chaenocephalus aceratus. The results support a distinct temperature-dependence of the topological features in the two proteins, suggesting different adaptations to cold and warm environments

Towards a molecular dynamics consensus view of B-DNA flexibility

We present a systematic study of B-DNA flexibility in aqueous solution using long-scale molecular dynamics simulations with the two more recent versions of nucleic acids force fields (CHARMM27 and parmbsc0) using four long duplexes designed to contain several copies of each individual base pair step. Our study highlights some differences between pambsc0 and CHARMM27 families of simulations, but also extensive agreement in the representation of DNA flexibility. We also performed additional simulations with the older AMBER force fields parm94 and parm99, corrected for non-canonical backbone flips. Taken together, the results allow us to draw for the first time a consensus molecular dynamics picture of B-DNA flexibilit

Role of stacking interactions in the binding sequence preferences of DNA bis-intercalators: insight from thermodynamic integration free energy simulations

The major structural determinant of the preference to bind to CpG binding sites on DNA exhibited by the natural quinoxaline bis-intercalators echinomycin and triostin A, or the quinoline echinomycin derivative, 2QN, is the 2-amino group of guanine (G). However, relocation of this group by means of introduction into the DNA molecule of the 2-aminoadenine (=2,6-diaminopurine, D) base in place of adenine (A) has been shown to lead to a drastic redistribution of binding sites, together with ultratight binding of 2QN to the sequence DTDT. Also, the demethylated triostin analogs, TANDEM and CysMeTANDEM, which bind with high affinity to TpA steps in natural DNA, bind much less tightly to CpI steps, despite the fact that both adenosine and the hypoxanthine-containing nucleoside, inosine (I), provide the same hydrogen bonding possibilities in the minor groove. To study both the increased binding affinity of 2QN for DTDT relative to GCGC sites and the remarkable loss of binding energy between CysMeTANDEM and ICIC compared with ATAT, a series of thermodynamic integration free energy simulations involving conversions between DNA base pairs have been performed. Our results demonstrate that the electrostatic component of the stacking interactions between the heteroaromatic rings of these compounds and the bases that make up the intercalation sites plays a very important role in the modulation of their binding affinities

Role of stacking interactions in the binding sequence preferences of DNA bis-intercalators: insight from thermodynamic integration free energy simulations

The major structural determinant of the preference to bind to CpG binding sites on DNA exhibited by the natural quinoxaline bis-intercalators echinomycin and triostin A, or the quinoline echinomycin derivative, 2QN, is the 2-amino group of guanine (G). However, relocation of this group by means of introduction into the DNA molecule of the 2-aminoadenine (=2,6-diaminopurine, D) base in place of adenine (A) has been shown to lead to a drastic redistribution of binding sites, together with ultratight binding of 2QN to the sequence DTDT. Also, the demethylated triostin analogs, TANDEM and CysMeTANDEM, which bind with high affinity to TpA steps in natural DNA, bind much less tightly to CpI steps, despite the fact that both adenosine and the hypoxanthine-containing nucleoside, inosine (I), provide the same hydrogen bonding possibilities in the minor groove. To study both the increased binding affinity of 2QN for DTDT relative to GCGC sites and the remarkable loss of binding energy between CysMeTANDEM and ICIC compared with ATAT, a series of thermodynamic integration free energy simulations involving conversions between DNA base pairs have been performed. Our results demonstrate that the electrostatic component of the stacking interactions between the heteroaromatic rings of these compounds and the bases that make up the intercalation sites plays a very important role in the modulation of their binding affinities

Conformational landscape of small ligands: a multilevel strategy to determine the conformational penalty of bioactive ligands

Determining the conformational penalty required for adopting the bioactive conformation is still a challenging question in drug design, because a small uncertainty in this free energy component can lead to significant errors in the predicted activities. Herein, we use the Multilevel strategy, a methodology recently developed by our group, to explore the conformational preferences of ligands in solution, and to estimate the conformational cost of selecting the bioactive conformation

The relative flexibility of B-DNA and A-RNA duplexes: database analysis

An extensive analysis of structural databases is carried out to investigate the relative flexibility of B-DNA and A-RNA duplexes in crystal form. Our results show that the general anisotropic concept of flexibility is not very useful to compare the deformability of B-DNA and A-RNA duplexes, since the flexibility patterns of B-DNA and A-RNA are quite different. In other words, ‘flexibility' is a dangerous word for describing macromolecules, unless it is clearly defined. A few soft essential movements explain most of the natural flexibility of A-RNA, whereas many are necessary for B-DNA. Essential movements occurring in naked B-DNAs are identical to those necessary to deform DNA in DNA-protein complexes, which suggest that evolution has designed DNA-protein complexes so that B-DNA is deformed according to its natural tendency. DNA is generally more flexible, but for some distortions A-RNA is easier to deform. Local stiffness constants obtained for naked B-DNAs and DNA complexes are very close, demonstrating that global distortions in DNA necessary for binding to proteins are the result of the addition of small concerted deformations at the base-pair level. Finally, it is worth noting that in general the picture of the relative deformability of A-RNA and DNA derived from database analysis agrees very well with that derived from state of the art molecular dynamics (MD) simulation

Estratègies i recursos per a no nadius per a la impartició d'assignatures en anglès de química en els graus d'enginyeria

Una eina per aconseguir el domini d’una llengua estrangera, és l’aprenentatge integrat de continguts i llengües estrangeres. Aquesta comunicació es focalitza en l’experiència acadèmica adquirida a partir de la impartició del Grau d’Enginyeria Química a l’Escola Politècnica Superior d’Enginyeria de Manresa (UPC). L’estratègia seguida s’ha basat en la disponibilitat del professorat per impartir assignatures en anglès. Inicialment s’imparteix en anglès l’assignatura de Química ubicada en el primer quadrimestre. Això permet que a l’inici de la carrera, professorat i estudiantat comparteixin un glossari bàsic. Més endavant es familiaritzen amb el llenguatge de laboratori a l’assignatura d’Anàlisi Química Instrumental. El fet que les classes siguin en anglès aconsegueix, en la majoria d’hores de classe, que el nivell d’atenció sigui més alt i això s’ha reflectit en uns millors resultats acadèmics dels estudiants. Com a recursos han estat claus, en primer lloc, el curs “Intensive Interactive Teacher Speaking Skills & Strategies” (ICE, UPC) per estimular la impartició de classes en anglès. Segonament, s’ha disposat d’un recurs molt útil per donar classes de qualsevol assignatura en anglès, el “Class Talk” http://www.upc.edu/slt/classtalk/, elaborat per professors de l’EPSEM i el SLT de la UPC. També cal destacar el recurs anomenat “Multilingual Formulae” (http://mformulae.epsem.upc.edu), que defineix en anglès conceptes químics, fórmules, equacions i altres expressions simbòliques. Finalment s’han elaborat material de les assignatures en anglès (presentacions, apunts, llistat de problemes i guions de pràctiques) com a material suplementari per ajudar a la comprensió de las classes.Peer Reviewe

Merging Ligand-Based and Structure-Based Methods in Drug Discovery: An Overview of Combined Virtual Screening Approaches

Virtual screening (VS) is an outstanding cornerstone in the drug discovery pipeline. A variety of computational approaches, which are generally classified as ligand-based (LB) and structure-based (SB) techniques, exploit key structural and physicochemical properties of ligands and targets to enable the screening of virtual libraries in the search of active compounds. Though LB and SB methods have found widespread application in the discovery of novel drug-like candidates, their complementary natures have stimulated continued e orts toward the development of hybrid strategies that combine LB and SB techniques, integrating them in a holistic computational framework that exploits the available information of both ligand and target to enhance the success of drug discovery projects. In this review, we analyze the main strategies and concepts that have emerged in the last years for defining hybrid LB + SB computational schemes in VS studies. Particularly, attention is focused on the combination of molecular similarity and docking, illustrating them with selected applications taken from the literature

Lipophilicity in drug design: an overview of lipophilicity descriptors in 3D-QSAR studies

The pharmacophore concept is a fundamental cornerstone in drug discovery, playing a critical role in determining the success of in silico techniques, such as virtual screening and 3D-QSAR studies. The reliability of these approaches is influenced by the quality of the physicochemical descriptors used to characterize the chemical entities. In this context, a pivotal role is exerted by lipophilicity, which is a major contribution to host-guest interaction and ligand binding affinity. Several approaches have been undertaken to account for the descriptive and predictive capabilities of lipophilicity in 3D-QSAR modeling. Recent efforts encode the use of quantum mechanical-based descriptors derived from continuum solvation models, which open novel avenues for gaining insight into structure-activity relationships studies