title: A Practical Quantum Mechanics Molecular Mechanics Method for the Dynamical Study of Reactions in Biomolecules.
abstract: Quantum mechanics/molecular mechanics (QM/MM) methods are excellent tools for the modeling of biomolecular reactions. Recently, we have implemented a new QM/MM method (Fireball/Amber), which combines an efficient density functional theory method (Fireball) and a well-recognized molecular dynamics package (Amber), offering an excellent balance between accuracy and sampling capabilities. Here, we present a detailed explanation of the Fireball method and Fireball/Amber implementation. We also discuss how this tool can be used to analyze reactions in biomolecules using steered molecular dynamics simulations. The potential of this approach is shown by the analysis of a reaction catalyzed by the enzyme triose-phosphate isomerase (TIM). The conformational space and energetic landscape for this reaction are analyzed without a priori assumptions about the protonation states of the different residues during the reaction. The results offer a detailed description of the reaction and reveal some new features of the catalytic mechanism. In particular, we find a new reaction mechanism that is characterized by the intramolecular proton transfer from O1 to O2 and the simultaneous proton transfer from Glu 165 to C2.
authors.affiliation: Departamento de Física Teórica de la Materia Condensada and Condensed Matter Physics Center (IFIMAC), Universidad Autónoma de Madrid, Madrid, Spain; Molecular Modelling Group, Center of Molecular Biology "Severo Ochoa" (CSIC-UAM), Madrid, Spain.
authors.forename: Jesús I
authors.initials: JI
authors.lastname: Mendieta-Moreno
authors.affiliation: Molecular Modelling Group, Center of Molecular Biology "Severo Ochoa" (CSIC-UAM), Madrid, Spain.
authors.forename: Iñigo
authors.initials: I
authors.lastname: Marcos-Alcalde
authors.affiliation: Departamento de Física Teórica de la Materia Condensada and Condensed Matter Physics Center (IFIMAC), Universidad Autónoma de Madrid, Madrid, Spain.
authors.forename: Daniel G
authors.initials: DG
authors.lastname: Trabada
authors.affiliation: Molecular Modelling Group, Center of Molecular Biology "Severo Ochoa" (CSIC-UAM), Madrid, Spain.
authors.forename: Paulino
authors.initials: P
authors.lastname: Gómez-Puertas
authors.affiliation: Departamento de Física Teórica de la Materia Condensada and Condensed Matter Physics Center (IFIMAC), Universidad Autónoma de Madrid, Madrid, Spain. Electronic address: jose.ortega@uam.es.
authors.forename: José
authors.initials: J
authors.lastname: Ortega
authors.affiliation: Molecular Modelling Group, Center of Molecular Biology "Severo Ochoa" (CSIC-UAM), Madrid, Spain; Biomol-Informatics SL, Campus UAM, Madrid, Spain.
authors.forename: Jesús
authors.initials: J
authors.lastname: Mendieta
mesh_terms: D055162:Biocatalysis; D002244:Carbon / Q000737:chemistry; D018698:Glutamic Acid / Q000737:chemistry*; D006801:Humans; D056004:Molecular Dynamics Simulation; D010100:Oxygen / Q000737:chemistry; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D011522:Protons; D011789:Quantum Theory; D012984:Software; D013816:Thermodynamics; D014305:Triose-Phosphate Isomerase / Q000737:chemistry*
chemical_list: D011522:Protons; D018698:Glutamic Acid; D002244:Carbon; D014305:Triose-Phosphate Isomerase; D010100:Oxygen
keywords: Biomolecules; Catalytic mechanisms; DFT; Enzymatic reactions; Molecular dynamics; QM/MM; TIM