Accurate Reaction Energies in Proteins Obtained by Combining QM/MM and Large QM Calculations.
نویسندگان
چکیده
We here suggest and test a new method to obtain stable energies in proteins for charge-neutral reactions by running large quantum mechanical (QM) calculations on structures obtained by combined QM and molecular mechanics (QM/MM) geometry optimization on several snapshots from molecular dynamics simulations. As a test case, we use a proton transfer between a metal-bound cysteine residue and a second-sphere histidine residue in the active site of [Ni,Fe] hydrogenase, which has been shown to be very sensitive to the surroundings. We include in the QM calculations all residues within 4.5 Å of the active site, two capped residues on each side of the active-site residues, and all charged groups that are buried inside the protein, which for this enzyme includes three iron-sulfur clusters, in total, 930 atoms. These calculations are performed at the BP86/def2-SV(P) level, but the energies are then extrapolated to the B3LYP/def2-TZVP level with a smaller QM system, and zero-point energy, entropy, and thermal effects are added. We test three approaches to model the remaining atoms of the protein solvent, viz., by standard QM/MM approaches using either mechanical or electrostatic embedding or by using a continuum solvation model for the large QM systems. Quite encouragingly, the three approaches give the same results within 14 kJ/mol, and variations in the size of the QM system do not change the energies by more than 8 kJ/mol, provided that the QM/MM junctions are not moved closer to the QM system. The statistical precision for the average over 10 snapshots is 1-3 kJ/mol.
منابع مشابه
Quantum Mechanics-Molecular Mechanics Model Study of some Antibiotics and Vitamins in Gas Phases: Investigation of Energy and NMR Chemical Shift
The combination of Quantum Mechanics (QM) and Molecular Mechanics (MM) methods hasbecome alternative tool for many applications that pure QM and MM could not be suitable.The QM/MM method has been used for different type of problems, for example: structuralbiology, surface phenomena, and liquid phase. In this paper we have performed these methods forsome antibiotics and vitamins and then we comp...
متن کاملA QM/MM study of the binding of RAPTA ligands to cathepsin B
We have carried out quantum mechanical (QM) and QM/MM (combined QM and molecular mechanics) calculations, as well as molecular dynamics (MD) simulations to study the binding of a series of six RAPTA (Ru(II)-arene-1,3,5-triaza-7-phosphatricyclo-[3.3.1.1] decane) complexes with different arene substituents to cathepsin B. The recently developed QM/MM-PBSA approach (QM/MM combined with Poisson-Bol...
متن کاملDFT calculations on entire proteins for free energies of binding: application to a model polar binding site
In drug optimisation calculations, the Molecular Mechanics Poisson-Boltzmann Surface Area (MM-PBSA) method can be used to compute free energies of binding of ligands to proteins. The method involves the evaluation of the energy of configurations in an implicit solvent model. One source of errors is the force field used, which can potentially lead to large errors due to the restrictions in accur...
متن کاملMulticonfiguration Molecular Mechanics Based on Combined Quantum Mechanical and Molecular Mechanical Calculations.
The multiconfiguration molecular mechanics (MCMM) method is a general algorithm for generating potential energy surfaces for chemical reactions by fitting high-level electronic structure data with the help of molecular mechanical (MM) potentials. It was previously developed as an extension of standard MM to reactive systems by inclusion of multidimensional resonance interactions between MM conf...
متن کاملConverging ligand‐binding free energies obtained with free‐energy perturbations at the quantum mechanical level
In this article, the convergence of quantum mechanical (QM) free-energy simulations based on molecular dynamics simulations at the molecular mechanics (MM) level has been investigated. We have estimated relative free energies for the binding of nine cyclic carboxylate ligands to the octa-acid deep-cavity host, including the host, the ligand, and all water molecules within 4.5 Å of the ligand in...
متن کاملذخیره در منابع من
با ذخیره ی این منبع در منابع من، دسترسی به آن را برای استفاده های بعدی آسان تر کنید
عنوان ژورنال:
- Journal of chemical theory and computation
دوره 9 1 شماره
صفحات -
تاریخ انتشار 2013