Fragment molecular orbital (FMO) method for studying actinide interaction with DNAs and proteins

Due to its potential health and environmental impacts, actinide binding to biomolecules has been a subject of intensive investigations. A large number of experimental works have been carried out but our understanding remains mostly in a macroscopic scale. Modeling actinide interaction with large biomolecules using ab initio quantum chemical calculations may drastically expand our molecular level knowledge but is challenged by a demand for huge computational resources.
Our strategy to overcome this difficulty is to apply fragment molecular orbital (FMO) method. In FMO, the molecular system of interest is partitioned into small fragments. Each fragment and fragment pair is subject to self-consistent field calculations under environmental electrostatic potentials and the electronic structure of the whole system is reconstituted [1]. This procedure drastically reduces computational cost of Hartree Fock calculations from N³ to N² (or less) and is readily parallelizable. FMO has been extended to MP2 and to DFT to include electron correlation and was successfully applied to the systems such as hydrated DNA (~ 7500 atoms) [2].
Currently we are upgrading the FMO program Abinit-MP [3] to implement 5f elements into the program. We first choose uranyl-bound DNA for a case study. Calcu-lations are performed as follows. UO₂ ²⁺-bound d(CGCGAATTCGCG)2 (Dickerson-Drew dodecamer) with 20 Na⁺ ions and SPC/E water shell with 10 Å thickness (a to-tal of 15559 atoms in the system) is first thermally equilibrated and subsequently submitted to molecular dynamics (MD) simulation at 300 K for 100 ns interval using AMBER 14 program. Force field parameters for UO₂ ²⁺ and coordinating water are those developed by Pomogaev et al. [4]. At each 1 ns time step of MD simulation, the structure is extracted and submitted to FMO single point energy calculation at the MP2 level. In FMO, nucleic unit is appropriately divided into sugar, base, and phosphate fragments. Inter-fragment interaction energy analysis is performed to explore the binding affinity of uranyl to DNA and its influence on base pairing.
Binding of Eu³⁺ to Calmodulin and its comparison with Ca²⁺ binding is under in-vestigation.

FMO program Abinit-MP and its graphical user interface BioStationViewer are freely distributed online [5]. This project is funded by the Ministry of Education, Culture, Sports, Science, and Technology of Japan (MEXT).