Search results for "Free energy perturbation"
showing 7 items of 7 documents
Peptide Bond Formation Mechanism Catalyzed by Ribosome
2015
In this paper we present a study of the peptide bond formation reaction catalyzed by ribosome. Different mechanistic proposals have been explored by means of Free Energy Perturbation methods within hybrid QM/MM potentials, where the chemical system has been described by the M06-2X functional and the environment by means of the AMBER force field. According to our results, the most favorable mechanism in the ribosome would proceed through an eight-membered ring transition state, involving a proton shuttle mechanism through the hydroxyl group of the sugar and a water molecule. This transition state is similar to that described for the reaction in solution (J. Am. Chem. Soc. 2013, 135, 8708–871…
Conformational equilibrium of chorismate. A QM/MM theoretical study combining statistical simulations and geometry optimisations in gas phase and in …
2003
We report a theoretical study on the conformational equilibrium of chorismate that precedes its rearrangement to prephenate, an important enzyme-catalyzed reaction. In first place we show that the usual classification of chorismate conformers based on the relative position of the hydroxyl and ether bridge, pseudo-diaxial and pseudo-diequatorial, is not the only relevant factor from the point of view of the a posteriori rearrangement. Here we also analyse another complementary geometrical classification based on the interatomic distance between the carbon atoms to be bounded. Using the umbrella sampling approach and this distance as distinguished internal reaction coordinate, the gas phase A…
Suitability ofMMGBSAfor the selection of correct ligand binding modes from docking results
2018
The estimation of the correct binding mode and affinity of a ligand into a target protein using computational methods is challenging. However, docking can introduce poses from which the correct binding mode could be identified using other methods. Here, we analyzed the reliability of binding energy estimation using the molecular mechanics-generalized Born surface area (MMGBSA) method without and with energy minimization to identify the likely ligand binding modes within docking results. MMGBSA workflow (a) outperformed docking in recognizing the correct binding modes of androgen receptor ligands and (b) improved the correlation coefficient of computational and experimental results of rescor…
Molecular Mechanism of the site-specific self-cleavage of the RNA phosphodiester backbone by a Twister Ribozyme
2017
Published as part of the special collection of articles derived from the 10th Congress on Electronic Structure: Principles and Applications (ESPA-2016). The catalytic activity of some classes of natural RNA, named as ribozymes, has been discovered just in the past decades. In this paper, the cleavage of the RNA phosphodiester backbone has been studied in aqueous solution and in a twister ribozyme from Oryza sativa. The free energy profiles associated with a baseline substrate-assisted mechanism for the reaction in the enzyme and in solution were computed by means of free energy perturbation methods within hybrid QM/MM potentials, describing the chemical system by the M06-2× functional and t…
Redox potentials and acidity constants from density functional theory based molecular dynamics.
2014
CONSPECTUS: All-atom methods treat solute and solvent at the same level of electronic structure theory and statistical mechanics. All-atom computation of acidity constants (pKa) and redox potentials is still a challenge. In this Account, we review such a method combining density functional theory based molecular dynamics (DFTMD) and free energy perturbation (FEP) methods. The key computational tool is a FEP based method for reversible insertion of a proton or electron in a periodic DFTMD model system. The free energy of insertion (work function) is computed by thermodynamic integration of vertical energy gaps obtained from total energy differences. The problem of the loss of a physical refe…
Increased Acid Dissociation at the Quartz/Water Interface.
2018
As shown by a quite significant amount of literature, acids at the water surface tend to be “less” acid, meaning that their associated form is favored over the conjugated base. What happens at the solid/liquid interface? In the case of the silica/water interface, we show how the acidity of adsorbed molecules can instead increase. Using a free energy perturbation approach in combination with electronic structure-based molecular dynamics simulations, we show how the acidity of pyruvic acid at the quartz/water interface is increased by almost two units. Such increased acidity is the result of the specific microsolvation at the interface and, in particular, of the stabilization of the deprotona…
Theoretical studies of HIV-1 reverse transcriptase inhibition
2012
Computational methods for accurately calculating the binding affinity of a ligand for a protein play a pivotal role in rational drug design. We herein present a theoretical study of the binding of five different ligands to one of the proteins responsible for the human immunodeficiency virus type 1 (HIV-1) cycle replication; the HIV-1 reverse transcriptase (RT). Two types of approaches are used based on molecular dynamics (MD) simulations within hybrid QM/MM potentials: the alchemical free energy perturbation method, FEP, and the pathway method, in which the ligand is physically pulled away from the binding site, thus rendering a potential of mean force (PMF) for the binding process. Our com…