**3.5 Hydration of Ln(III)**

The lanthanide contraction and the gadolinium break have attracted considerable attention in the inorganic chemistry. As an application of the 4f-in-core MCP (Fujiwara *et al.*, 2011), a series of FMO3-MD simulations on droplet model of Ln(III) plus 64 water molecules have been underway at the HF level (Fujiwara *et al.*, in preparation). The RDF peal positions for La(III) (nona-hydration) and Lu(III) (octa-hydration) were estimated to be 2.59 Å and 2.31 Å, respectively, and they were comparable to the corresponding experimental values of 2.54 Å and 2.31 Å. Interestingly, the octa- and nona-hydration results for Gd(III) were evaluated as 2.46 Å and 2.53 Å, respectively. The former value is in closer agreement with the experimental value of 2.42 Å, suggesting that the octa-hydration is preferable.

#### **3.6 Comparison on hydration dynamics of** *cis-* **and** *trans***-platin**

FMO-MD has also given important insight into the difference in the hydration dynamics of *cis*- and *trans*-platin (Mori *et al.*, 2012). Since *cis*-platin (*cis*-[PtIICl2(NH3)2]) is recognized as an anticancer substance, quite a few studies have been devoted to the biochemical functions of its derivatives. Particularly interesting in the pharmaceutical research field of Pt-based anticancer drugs is the behaviour of its geometrical isomer, *trans*-platin, which only shows very low anticancer activity (Fig. 11). *Trans*-platin had not been considered to form DNA adducts that lead to anticancer activity. However, *trans*-type Pt-complexes that shows antitumor activities was found recently. Despite the extensive research on both *cis-* and *trans*-platin, the origin of their difference in biochemical activity still remains unclear. The final step of the antitumor treatment is the combination of *cis*-platin and DNA leading modifications of the DNA structure. Meanwhile, some earlier steps, such as solvation before reaching the final target, are also believed to play important roles in the efficacy of drugs.

fluctuation with a larger extent of electron donation (net charge of 1.3-1.4). Discussion with

Fig. 10. Zn-O RDFs and coordination numbers (CN) calculated by FMO2/3-MD simulations.

The lanthanide contraction and the gadolinium break have attracted considerable attention in the inorganic chemistry. As an application of the 4f-in-core MCP (Fujiwara *et al.*, 2011), a series of FMO3-MD simulations on droplet model of Ln(III) plus 64 water molecules have been underway at the HF level (Fujiwara *et al.*, in preparation). The RDF peal positions for La(III) (nona-hydration) and Lu(III) (octa-hydration) were estimated to be 2.59 Å and 2.31 Å, respectively, and they were comparable to the corresponding experimental values of 2.54 Å and 2.31 Å. Interestingly, the octa- and nona-hydration results for Gd(III) were evaluated as 2.46 Å and 2.53 Å, respectively. The former value is in closer agreement with the

FMO-MD has also given important insight into the difference in the hydration dynamics of *cis*- and *trans*-platin (Mori *et al.*, 2012). Since *cis*-platin (*cis*-[PtIICl2(NH3)2]) is recognized as an anticancer substance, quite a few studies have been devoted to the biochemical functions of its derivatives. Particularly interesting in the pharmaceutical research field of Pt-based anticancer drugs is the behaviour of its geometrical isomer, *trans*-platin, which only shows very low anticancer activity (Fig. 11). *Trans*-platin had not been considered to form DNA adducts that lead to anticancer activity. However, *trans*-type Pt-complexes that shows antitumor activities was found recently. Despite the extensive research on both *cis-* and *trans*-platin, the origin of their difference in biochemical activity still remains unclear. The final step of the antitumor treatment is the combination of *cis*-platin and DNA leading modifications of the DNA structure. Meanwhile, some earlier steps, such as solvation before reaching the final target, are also believed to play important roles in the efficacy of drugs.

experimental value of 2.42 Å, suggesting that the octa-hydration is preferable.

**3.6 Comparison on hydration dynamics of** *cis-* **and** *trans***-platin** 

NPA was found to be preferable for hydrated metal ions.

Reproduced from Fujiwara *et al.* (2010b) by permission.

**3.5 Hydration of Ln(III)**

Their hydration should be investigated to understand the difference in the medical application between *cis*- and *trans*-platins.

Fig. 11. Structures of *cis*- and *trans*-platins and schematic representations of DNA adducts. Reproduced from Mori *et al.* (2012) by permission.

FMO-MD simulations were performed for hydrated *cis*- and *trans*-platins. The simulation conditions were set as described below. Each platin complex was hydrated with a spherical droplet of water centred at the Pt atom with a diameter of 10.5 Å. This diameter was determined to include up to the second solvation shell, so that the physicochemical properties of the first shell should be reproduced. In the FMO-MD simulations, the electronic states of the hydrated platin complexes were described by FMO(3)-MP2. The basis sets were MCPdz for Pt, MCPdzp for Cl, and 6-31G(d) for the others, respectively. The MCP basis sets were applied for heavy elements (see subsection 2.2.6). The central platin and each of the water molecules were regarded as independent fragments. DF was applied to allow for the generation of proton-transferred species during the production MD runs. For each *cis*- and *trans*-platin system, a 1-ps equilibration and a subsequent 2-ps production MD run were performed using the Nose-Hoover Chains NVT ensemble at 300 K. NPA was also performed during the FMO-MD run to analyze the differences in charge fluctuations between *cis*- and *trans*-platin, illuminating the differences in the hydration environment around polarized Pt+-Cl bonds, which should be cleaved by the nucleophilic attack of a solvent water molecule.

The time evolution of the natural charge on each ligand in *cis*- and *trans*-platin, and that of Pt-Cl bond lengths are shown in Fig. 12. Relatively larger charge fluctuations were observed on the Pt/Cl sites than on the NH3 sites in both platins. This difference among the sites was attributable to the fact that NH3 has no amplitude in the highest occupied molecular orbital. A close comparison of the left and right graphs in Fig. 12 revealed a correlation between fluctuation of the Pt/Cl sites and that of the Pt-Cl bond. By applying the Fourier transform technique to the charge fluctuation, we calculated the frequency of the fluctuation to be 334 cm-1. This frequency can also be assigned to the Pt-Cl stretching mode coupled with intermolecular vibrations between the solute platin and solvent water molecules. The correlation observed in charge fluctuation on Pt and Cl sites means that there is a CT interaction between them. Since the frontier MO that participates in the CT process is a Pt-Cl antibonding orbital, the CT interaction coupled with the fluctuation of the solvent water should induce a Pt-Cl bonds fluctuation. Since *trans*-platin has inversion symmetry, the

Recent Advances in Fragment Molecular

features.

**5. Acknowledgment** 

**6. References** 

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No. 6, (August 2004), pp. 2483-2490, ISSN 1089-7690

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Orbital-Based Molecular Dynamics (FMO-MD) Simulations 19

In conclusion, FMO-MD is a highly-parallelizable *ab initio* MD method. FMO-MD has advanced rapidly by improvement of both the FMO and MD portions of the method and has been successfully applied to various chemical phenomena in solution. We are planning to extend the methodology and application of FMO-MD by incorporating several new

Thanks are due to Dr. Makoto Sato, Mr. Takayuki Fujiwara, Mr. Yuji Kato, and Professor Hiroshi Yamataka of Rikkyo University, Dr. Yoshio Okiyama of Tokyo University, Ms. Natsumi Hirayama of Ochanomizu University, Professor Takeshi Ishikawa of Gifu University, and Dr. Takatoshi Fujita and Professor Shigenori Tanaka of Kobe University for their collaboration in the FMO-MD project. The works presented in this articles have been supported by the following funds: the Core Research for Evolutional Science and Technology (CREST) project of the Japan Science and Technology Agency (JST) to YK, YM, TK, and HM; the Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan (MEXT) to YM ("Molecular Theory for Real Systems") and to YM and YK ("Molecular-level analyses of dynamics-controlled organic reactions"); the Ocha-dai Academic Production project by JST, Funding from Sumitomo Foundation, and Advanced Scientific Computing project 2010 at the Research Institute for Information Technology of Kyushu University to HM; the Rikkyo University Special Fund for Research (SFR) to YM, YK, and HM; and the Research and Development of Innovative Simulation Software (RISS) project at the Institute of Industrial Science of the University of Tokyo to TN and YM. Some of the calculations were performed using computing resources at the Research Centre for Computational Science, Okazaki, Japan.

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dipole moment of *trans*-platin is much smaller than that of *cis*-platin. This means that the number of water molecules which coordinates to the platin complex is larger for *cis*-platin than for *trans*-platin. Thus, the CT interaction coupled with the solvent motion is stronger in *cis*-platin than in *trans*-platin. As a result, the Pt-Cl bonds are easier to elongate for the cleavage in the hydrated *cis*-platin than in the hydrated *trans*-platin. Thus, by using FMO-MD simulations, we obtained new quantum chemical insight into the solvation of platin complexes.

Fig. 12. (Left) Time evolution of natural charge on the Pt, NH3, and Cl sites in the *cis*- and *trans*-platin. Solid and dotted lines indicate *cis*- and *trans*- isomers, respectively. (Right) Time evolution of Pt-Cl bond lengths. Reproduced from Mori *et al.* (2012) by permission.
