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First-principles and hybrid QM/MM Molecular Dynamics Studies of Nucleic AcidsThe overall project objective is to increase the understanding of functional nucleic acid systems, i.e. designed RNA and DNA sequences. This is done using state-of-the-art electronic structure studies, mostly first-principles and hybrid QM/MM molecular dynamics simulations. A second goal is to contribute to the development of ab-initio molecular dynamics and multi-scale QM/MM extensions to the field of electronic structure calculations. In this project we employ the aforementioned First-principles and Hybrid QM/MM molecular dynamics methods to study ribozymes, RNA molecules that can catalyze nucleolytic reactions. Ribozymes cleave target mRNA in a highly sequence-specific manner, which bears potential for novel pharmaceutical agents in therapies against oncogenes and HIV. Despite a large experimental effort to characterize the catalytic mechanisms of ribozymes and the role of metal-ions, a number of issues remain unsettled. The maintenance of genomic integrity is of crucial importance to all organisms. DNA damage is constantly inflicted by a large number of endogenous and exogenous agents. One such endogenous reaction is hydrolysis, where the glycosidic bond of purine nucleotides is prone to acid-catalysed hydrolysis. Exogenous ionizing radiation, such as UV radiation from sunlight, impinging on living cells produces secondary low-energy electrons that may cause lethal DNA lesions. Therefore, secondly we also study DNA damage from hydrolysis and low-energy electrons. First-Principles and Hybrid QM/MM Molecular DynamicsOne of the routinely applied theoretical techniques in the study of biological systems is molecular dynamics (MD) simulations. In this approach, the system is propagated according to the laws of classical mechanics over a given potential energy surface. Solving the equations of motion allows one to obtain the dynamic and thermodynamic ensemble properties. Depending on the way in which the interaction potential between the particles is obtained, MD methods can be divided into two classes - classical or first-principles MD methods. In classical MD, the by-far most common approach, the potential energy surface is parameterized through an empirical fit of appropriately chosen analytic potential functions. Classical MD methods are very successful for the simulation of many properties of biological systems, but are intrinsically restricted to situations were no significant changes of the electronic structure occur. But many key processes, for example the breaking and forming of chemical bonds during chemical reactions, are accompanied by rearrangements in the electronic structure and can only be treated adequately by a complete quantum mechanical description. A recently developed generation of MD methods are therefore based directly on quantum mechanics - first-principles or ab-initio molecular dynamics. Here all the interactions are calculated from an electronic structure method, in most of the current implementations density functional theory (DFT). These simulations are therefore parameter-free and, in contrast to conventional electronic structure calculations which provide a static map of the potential surface of a reaction in the zero temperature limit, allow the direct inclusion of finite temperature effects. As it is in fact the finite temperature free energy profile of a system that determines rate constants and other thermodynamic properties this is a crucial extension, in particular for the realistic simulation of biological systems under, at least close to, physiological conditions.Due to computational expense the simulations of biological systems are often stripped down to a small model system of e.g. the active site of an enzyme with complete or partial neglect of the effects of the surroundings. One approach to obtain a more realistic description of the molecular environment is to adopt a combined quantum mechanics and molecular mechanics (QM/MM) method. In such a hybrid QM/MM method the active site region is treated within a full quantum mechanical calculation while the electrostatic potential and van der Waals interaction from the remainder of the system is determined using a more expedient classical force-field calculation. The two systems are allowed to interact, allowing the evolution of the MM-system to effect the QM-system and vice-versa. The promise of this combined method is therefore an exact treatment of the active site while modeling the role of the extended system in a very computationally efficient way. |
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