1,721,155 research outputs found
Protein-protein interactions as a drug target: A molecular modeling approach
No full textThis review is devoted to the computer aided design of drugs targeting protein-protein interactions (PPIs). General features of PPIs are discussed in the introduction, then the problems of protein interfaces druggability and design techniques application are addressed, and finally a case of active peptides design is described
Atomic level description of osmolytes protecting effect against thermal denaturation of proteins
No full textDevelopment of a Coarse-Grained Molecular Dynamics (CG-MD) approach to explore tubulin-ligand binding
Full text linkMicrotubules (MTs) are highly dynamic polymers that regulate numerous cellular functions, such as intracellular cargo trafficking and cell proliferation [1]. Tubulin αβ-heterodimer is the fundamental structural unit of MTs and small molecules’ binding to this protein can regulate dynamically growth and shrinkage of MTs, with important therapeutic implications [2]. Indeed, over the last decades many ligands with diverse chemical scaffolds have been investigated and eight binding sites have been experimentally characterized [3]. Further advances in the therapeutic development for this strategic target require the assistance of computational methods.
Current in-silico investigations, such as docking or All-Atom Molecular Dynamics (AA-MD), are limited by either the conformational complexity of the investigated ligand or by the timescales that can be effectively simulated. An alternative approach is offered by Coarse-Grained Molecular Dynamics (CG-MD). By grouping several atoms into a smaller number of beads, this method allows to reduce the cost of simulation by three orders of magnitude [4]. In particular, the Martini 3 model was shown to be a good compromise between reduction of complexity and maintenance of chemical accuracy [5].
The objective of this ongoing Ph.D. project is to develop a computational approach with the Martini 3 model to investigate the binding of small molecules to the tubulin αβ-heterodimer. In particular, the first target is to elucidate the binding pathway of the alkaloid drug colchicine to its experimentally known binding site. Preliminary results show how unbiased CG-MD simulations of colchicine molecules can identify long-lived interaction sites near the known binding pocket. Current efforts focus on the investigation of these poses with enhanced sampling methods to elucidate the complete binding pathway.
If this in-silico approach will be validated, it could provide a novel and multiscale approach to investigate the binding of innovative ligand candidates without a priori knowledge of their binding site, leveraging the reduced cost of CG-MD to efficiently identify meaningful starting points for more refined and computationally intensive methods.
References
[1] Janke, C., Journal of Cell Biology 2014, 206(4): 461-472 [doi: 10.1016/j.tcb.2018.05.001]
[2] Steinmetz, M. O., et al, Trends in Cell Biology 2018, 28(10): 776–792 [doi: 10.1016/j.tcb.2018.05.001]
[3] Pérez‐Peña, H., et al, Biomolecules 2023, 13(2): 285 [doi: 10.3390/biom13020285]
[4] Ingólfsson, H.I., et al, WIREs Comput Mol Sci 2014, 4: 225-248 [doi: 10.1002/wcms.1169]
[5] Souza, P.C.T., et al, Nat Commun 2020, 11: 3714 [doi: 10.1038/s41467-020-17437-5
Solvent effect on halogen bonding : the case of the I···O interaction
No full textThe solvent effect on the I⋯O halogen bonding in complexes of iodobenzene derivatives with formaldehyde has been investigated by systematically varying the substituents on the iodobenzene ring. Calculations have been performed at MP2 and DFT levels of theory, using the aug-cc-pVDZ basis set and the pseudopotential for iodine. Within the DFT approach, a series of the most widely used exchange-correlation functionals have been considered, comprising PBE, PBE0, B3LYP, BH&HLYP, M06-2X and M06-HF. Results obtained in diethylether and in water using the conductor-like polarizable continuum model (CPCM) have been compared with in vacuo results. Though halogen bonding distances were found to systematically shorten when moving from vacuo to diethylether and then to water, the associated interaction energies showed a decrease in absolute value, indicating that solvent has a destabilizing effect on this interaction. By comparison with MP2 results, all the considered functionals, B3LYP excepted, have been found adequate to describe halogen bonding. As far as the interaction energies are concerned, the best performance was obtained with the M06-HF functional in vacuo and the PBE functional in solution. The geometrical parameters characterizing halogen bonds were better reproduced by the M06-2X functional
Modelling the effect of osmolytes on peptide mechanical unfolding
No full textOsmolyte mols. can be classified in two different groups with respect to their effect on protein stability: osmoprotectants, which stabilize the protein or peptide folded state, and denaturants, which favor the denatured state. Mech. unfolding free energy of a model peptide has been obtained from umbrella sampling and weighted histogram anal. method, and the effect of four different osmolytes on the free energy difference between the folded and the denatured state have been calcd. The obsd. trend mirrors the expected behavior of the studied osmolytes and unfolding pathways anal. allows an insight in the osmolyte action mechanism
Chiral doping of nematic phases and its application to the determination of absolute configuration
No full textDoping nematic liquid crystals with nonracemic chiral compounds induces a twisted nematic (cholesteric) phase. The ability of solutes to twist the nematic phase may be related to the overall shape of the chiral dopant and consequently to its absolute configuration. The cholesteric induction is therefore a powerful tool complementary to chiroptical techniques to obtain stereochemical information on chiral molecules
Modelling protein-protein interactions
No full textProtein-protein interactions are fundamental to many biological processes, from signal transduction to cytoskeleton assembly and are therefore important targets for pharmaceutical research1. Particular attention is given here to the network of interactions occurring between tubulin dimers, in order to understand the nature of their association to form microtubules (MTs), polymeric cellular structures involved in mitosis. Given their primary importance in cell division, microtubules are interesting targets for antimitotic agents to be used in cancer therapies2. Currently, most of the MTs targeted drugs in use derive from screenings of natural compounds or their modifications. Following a different approach, we present here an in silico design of novel peptides able to interfere with MTs dynamic, thus acting as inhibitors of cancer cells proliferation. A molecular dynamics (MD) simulation was carried out on a system composed of two tubulin dimers in explicit water solvent, followed by interdimer binding energy evaluations and computational alanine scanning3 of the interface residues. It resulted that the binding energy is not evenly distributed over the protein-protein interface, but is concerntrated on some crucial amino acids, determinant for subunits association, defined as “hot-spots”. A subsequent simulation of a tubulin tetramer in complex with a vinblastine molecule in its active site pointed out how this antimitotic agent strongly reduces the number of interactions, thus explaining its microtubule destabilizing properties. Protein subsequences including a number of hot-spots were then used as a starting point for the development of peptides that could target different sites on tubulin with respect to vinblastine and other traditional chemoteherapeutic agents. The so designed peptides underwent further MD simulations in complex with tubulin, in order to evaluate if they conserved binding ability even when no longer inserted in the protein structure. The most promising ones were then sinthesized and underwent biological tests proving their ability to effectively alter MTs morphology and stability
Halogen Bonds with Benzene : an Assessment of DFT Functionals
No full textThe performance of an extensive set of density functional theory functionals has been tested against CCSD(T) and MP2 results, extrapolated to the complete basis set (CBS) limit, for the interaction of either DCl or DBr (D = H, HCC, F, and NC) with the aromatic system of benzene. It was found that double hybrid functionals explicitly including dispersion, that is, B2PLYPD and mPW2PLYPD, provide the better agreement with the CCSD(T)/CBS results on both energies and equilibrium geometry, indicating the importance of dispersive contributions in determining this interaction. Among the less expensive functionals, the better performance is provided by the ωB97X and M062X functionals, while the ωB97XD and B97D functionals are shown to work very well for bromine complexes but not so well for chlorine complexes
- …
