Asymmetric Environmental Effects on the Structure and Vibrations of

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Asymmetric Environmental Effects on the Structure and Vibrations of cis-[Pt(NH)Cl] in Condensed Phases 3

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Chao Zhang, Emmanuel Baribefe Naziga, and Leonardo Guidoni J. Phys. Chem. B, Just Accepted Manuscript • DOI: 10.1021/jp500865v • Publication Date (Web): 21 Aug 2014 Downloaded from http://pubs.acs.org on August 24, 2014

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The Journal of Physical Chemistry

Asymmetric Environmental Effects on the Structure and Vibrations of cis-[Pt(NH3)2Cl2] in Condensed Phases Chao Zhang,∗,†,¶ Emmanuel Baribefe Naziga,†,§ and Leonardo Guidoni∗,†,‡

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Physics Department, Sapienza-Universita di Roma, P. le A. Moro 5, 00185, Rome, Italy, and Department of Physical and Chemical Sciences, University of L’Aquila, Via Vetoio, 67100, L’Aquila, Italy E-mail: [email protected]; [email protected]

∗

To whom correspondence should be addressed Physics Department, Sapienza-Universita di Roma, P. le A. Moro 5, 00185, Rome, Italy ‡ Department of Physical and Chemical Sciences, University of L’Aquila, Via Vetoio, 67100, L’Aquila, Italy ¶ Current address: Institute of Physical Chemistry and Center for Computational Sciences, Johannes Gutenberg University Mainz, Staudinger Weg 7, D-55128, Mainz, Germamy § Current address: Department of Chemistry and Biochemistry, University of Lethbridge, 4401 University Drive, AB T1K 3M4, Lethbridge, Canada †

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Abstract

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We reported here the structural and vibrational properties of anti-cancer drug cis-

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platin (cis-[Pt(NH3 )2 Cl2 ]) in gas phase, in solid phase and in aqueous solution using

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DFT calculations, QM/MM molecular dynamics and effective normal modes analysis.

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In contrast with the gas phase case, asymmetric hydrogen bonding environments are

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found in both solid phase and aqueous solution. It is shown that the discrepancy of

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the molecular geometry between previous gas phase calculations and the X-ray crystal

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structure can be resolved by considering intermolecular hydrogen bonds in the calcu-

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lations of solid phase. In addition, our simulations in solid phase and aqueous solution

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reveal that asymmetric environmental effects lead to several spectral features observed

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in experiments, such as the blue-shift in the N-H stretching region and the frequency

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splitting of NH3 symmetric deformation modes. Furthermore, a similar decoupling and

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localization of several vibrational modes of cisplatin is found in solid phase and aqueous

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solution, in comparison to those of O−H stretching modes of water molecules in liquid

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water (J. Phys. Chem. Lett., 2013, 4(19), pp 3245-3250).

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KEYWORDS: Ab initio molecular dynamcis, vibrational spectroscopy, biomolecular sol-

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vation, water dynamics.

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Introduction

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Cisplatin (cis-diamminedichloroplatinum(II) or cis-DDP) is a widely used anti-tumoral agent

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in the therapy of various cancers since the discovery by Rosenberg and co-workers in 1960s. 1,2

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Its structure consists of a square-planar central platinum(II) binding to two chlorine ligands

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and two ammonia ligands in the cis-conformer. During the action, cisplatin molecule replace

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the two chlorine ions with a pair of purine nitrogen atoms of DNA bases, inducing damages

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and triggering cell death. 3,4

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To understand better the mode of action, vibrational spectroscopies i.e. infra-red (IR)

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and Raman, have been used to detect the intermediates, to measure the kinetics in drug 2


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delivery and to identify the binding modes. 5 One particular difficulty of applying vibrational

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spectroscopy in biochemical systems is the interpretation of the experimental spectra. 6 To

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this end, computational methods could offer great assistances. 7–14

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Structural and vibrational properties of cisplatin have been addressed in several compu-

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tational studies. Early efforts on the structural and electronic properties of cisplatin were

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contributed by Carloni et al. using density functional theory (DFT) . 15 Later on, the bind-

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ing of cisplatin to DNA was investigated by Quantum Mechanical/Molecular Mechanical

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(QM/MM) Car-Parrinello molecular dynamics (MD). 16 Other computational works also in-

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vestigated the hydrolysis process of cisplatin 17 and the structure of its hydration shell. 18

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From the point of view of an isolated molecule, a comprehensive ab initio quantum chemical

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analysis was given by Pavankumar et al. 19 A systematic evaluation of the performance of

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different exchange-correlation functionals for cisplatin by Michalska and Wysokiński 20 con-

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cluded that the MPW1PW/LanLDZ combination gave the best agreement with experiment

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for structural and vibrational properties. Further discussions on the choice of basis sets and

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effective core potentials were also reported by several groups. 21–23 Assessments on methods

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for calculating Raman intensities was reported 24 and all-electron basis sets calculations in

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gas phase were compared with newly measured Raman spectrum in solid phase. 25

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So far, all reported vibrational studies of cisplatin are restricted to gas phase calculations,

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although experimental spectra were collected in solid phase 25–29 and in aqueous solution. 30,31

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Conceivably, the missing of environmental effects could be an important source for the ob-

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served discrepancy between theoretical calculations and experimental measurements. 19,25

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Moreover, it would be desirable to establish the structural and vibrational properties of

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cisplatin in aqueous solution, where it acts as an anti-cancer drug. 3,4

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In this work, we focused on structural and vibrational properties of cisplatin in condensed-

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phase systems, i.e. solid phase and aqueous solution. The latter was treated by mixed

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QM/MM Car-Parrinello MD, which includes explicit solvent and possible anharmonicity

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effects at finite temperature. 32 This approach has been successfully used to calculate IR and

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Raman spectra of (bio)molecules aqueous solutions. 7,8,11,12,33–39 In addition, we employed

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the recently proposed effective normal modes analysis 11,40 to elucidate the finite temperature

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picture of vibrational motions of cisplatin and to interpret corresponding vibrational spectra.

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By comparing the condensed phase results with that of gas phase, we showed that both in

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solid phase and aqueous solution share a similar asymmetric hydrogen bonding environment.

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In solid state, such asymmetric environment originated from the asymmetric interactions

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of cisplatin in the molecular crystal due to packing effects. On the contrary, in aqueous

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solution, it is instead the hydrogen bonds (HBs) dynamics of the surrounding water molecules

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which instantaneously create an asymmetric field. These effects lead to the blue-shift in the

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N-H stretching region and the frequency splittings of NH3 symmetric deformation modes.

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Subsequently, they provide an interpretation of the corresponding experimental spectra in

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solid phase and aqueous solution.

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This article is organized as follows: Section 2 provides the theoretical background and

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computational protocols on the calculations of the IR and Raman spectra and vibrational

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analyses at 0K and finite temperature; Section 3 presents our results and discussions on

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asymmetric hydrogen bonding environments in solid phase and aqueous solution and their

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effects on structural and vibrational features of cisplatin molecule as observed in experiments.

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Conclusions and perspectives are given in Section 4.

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Computational methods

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Electronic structure calculations and QM/MM simulations

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Cisplatin in gas phase. Calculations using localized basis sets were performed using Den-

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sity Functional Theory (DFT) with Becke-Perdew (BP) exchange correlation functional. 41,42

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We used Gaussian package 43 with the LanL2DZ basis set according to the previous work

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from Wysokiński and coworkers. 20 In the Lan2DZ basis set, valence basis set and relativistic

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effective core potential (ECP) were used for the platinum atom. 44 The IR absorption coeffi4


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cient and Raman activity were subsequently obtained from these calculations. In plane wave

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calculations we used the CPMD program. 45 A cubic box of size 25 a.u. and a plane wave

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energy cut-off of 70 Ry were used. The BP exchange-correlation functional was employed in

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combination with Troullier-Martins pseudopotentials. 46 The system was isolated using the

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decoupling scheme by Martyna and Tuckerman. 47

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Cisplatin in solid phase. Geometry optimizations of cisplatin in solid phase were ini-

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tialized based on the alpha form of the crystal structure for non-hydrogen atoms. 48 Through-

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out the context of this work, we discussed only the structural and vibrational properties of

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alpha form which is energetically more stable than the beta form. Reader interested in

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polymorphism in cisplatin crystals could refer to recent literatures on this issue. 49,50 All cal-

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culations were performed using CPMD program 45 with BP exchange correlation functional

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and plane wave cutoff of 70 Ry. K-point meshes for Brillouin zone sampling were constructed

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using the Monkhorst-Pack 51 scheme with 2x2x2 and 4x4x4 grids. The inversion center of

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two cisplatin molecules in the unit cell was kept during geometry optimizations.

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Cisplatin in aqueous solution. QM/MM simulations of cisplatin in aqueous solu-

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tion were performed using the CPMD/Gromos interface. 45,52 A single cisplatin molecule was

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considered as the quantum system surrounded by 1606 TIP3P classical waters. 53 The sys-

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tem was firstly equilibrated by classical MD simulations at constant pressure (1 atm.) and

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temperature (300 K) using Nosé-Hoover thermostat 54 and Parrinello-Rahman barostat. 55

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Parameterization of cisplatin in the classical MD simulations followed the recommended

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AMBER procedure. 56 Most of the bond, angle and torsional parameters were adapted from

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classical MD simulations of cisplatin bound to DNA. 57 For bond and angle parameters of

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NH3 groups, standard AMBER values were adopted. 58

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The last frame of classical MD simulations was taken for subsequent QM/MM simula-

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tions. In QM/MM Car-Parrinello dynamics, we set the fictitious mass to 400 a.u and the

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time step to 0.085 fs. Other settings for QM region were the same as for the gas phase

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calculations. The QM/MM system was first equilibrated for 2 ps with Nosé-Hoover thermo-

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stat at 300 K. Then, the production run continued for 40 ps in NVE ensemble. The dipole

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moment of cisplatin was sampled along the simulation every two time steps. Snapshots from

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the trajectory were extracted every 10 time steps for analysis. For each snapshot, the polar-

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izability tensor of the cisplatin within the field generated by the classical point charges, was

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calculated using Gaussian 43 package, following the protocol described in ref. 38 For the pur-

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pose of checking the convergence of the sampling, the QM/MM simulation was prolonged

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for additional 40 ps. There are no significant differences in the shape of the VDOS (see

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Fig. S1 in Supporting Information), although details of the intensity depend on the length

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of samplings. This is in accord with the fact that 1 cm−1 spectral resolution in the Fourier

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transform of the time correlation function needs only 30 ps MD simulations. 32

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Calculation of IR spectra

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IR absorption coefficient for ith normal vibration in gas phase at zero temperature is given

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as 59 :

IiIR 120

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=C

dM dQi

2

(1)

where C is a constant, M is the electric dipole moment of the system and Qi are the normal coordinates. IR absorption spectrum at finite temperature in aqueous solution can be calculated from the fluctuation-dissipation theorem: 60

I

IR

(ω) = C

Z

∞

dte−iωt hM(t)M(0)i

(2)

−∞

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The final line shape should be multiplied by ω 2 /kT as a quantum correction 61,62 to the

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classical time-correlation function.

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Calculation of Raman spectra

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For a gas phase molecule at zero temperature, the classical expression of Raman scattering

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cross section of ith normal vibration over a solid angle dΩ is: 60 dσi (ω0 − ωi )4 =C dΩ ωi Bi

dα dQi

2

(3)

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where (ω0 − ωi )4 is the density of states and Bi = 1 − e−¯hωi /kT is a temperature factor

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which accounts for the intensity contribution of excited vibrational states for Raman Stokes

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intensity, 63 and α is the polarizability tensor.

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The corresponding Raman spectrum at finite temperature in aqueous solution can be obtained in a similar way to IR spectrum: 60,64 dσ = C(ω0 − ω)4 dΩ

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135

Z

∞ −∞

dte−iωt [ǫ0 · α(t) · ǫ][ǫ0 · α(0) · ǫ]

(4)

where ǫ0 and ǫ are the unit vectors in which the electric vector of incident light and of scattered light are polarized along.

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For spatially isotropic systems (liquids and gases) in the plan-polarization condition, i.e.

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the direction of the incident beam, the polarization direction of this beam, and the direction

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of observation are perpendicular to each other, the cross section can be rewritten as: dσ = C(ω0 − ω)4 dΩ

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Z

∞

dte−iωt hT rβ(0)β(t)i

(5)

−∞

where β is a traceless anisotropic part of the polarizability tensor α, β = α − α ¯ I (¯ α is the average of the polarizability tensor trace and I is the unit tensor). The final line shape should hω ¯ hω ¯ coth 2kT as a quantum correction 38,65 to the classical time-correlation be multiplied by 2kT function.

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In practice, hT rβ(0)β(t)i can be calculated as a sum of scalar auto-correlation functions.

hT rβ(0)β(t)i = hβxx (0)βxx (t) + βyy (0)βyy (t) + βzz (0)βzz (t)i (6)

+2 (hβyx (0)βyz (t) + βzx (0)βzx (t) + βzy (0)βzy (t)i)

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Vibrational analysis

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Vibrational normals modes of a given system at zero temperature can be found by solving

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the eigenvalue problem: 3N X

(7)

(hij − λk δij )νik = 0

i

1/2

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where hij is the mass-weighted molecular Hessian, λk

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the normal modes.

are the normal frequencies and νk

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At finite temperature, vibrational analysis is not straightforward. Here we used the re-

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cently proposed effective normal modes (ENM) analysis. 11,40 In this method, effective normal

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modes νk can be extracted from its vibrational density of states (VDOSs) by minimizing the

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following functional:

Ω(n) =

X k

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1 2πkT

Z

dω|ω|2n P ν˙ k (ω) −

1 2πkT

Z

dω|ω|n P ν˙ k (ω)

2 !

(8)

with respect to νk . Here n is an integer constant and P ν˙ k is VDOS of νk . When n=2, the method equals to the standard normal modes analysis with an average Hessian matrix.

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In practice, it is common to use internal coordinates such as bond lengths, bending

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angles and dihedral angles, i.e. Decius coordinates, 59 instead of cartesian coordinates for

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molecules. Furthermore, it is convenient to define another set of internal coordinates, i.e.

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Pulay coordinates 66 as linear combinations of Decius coordinates. The advantage using

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Pulay coordinates is that they reflect the the symmetry of the molecular functional groups

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and resemble the actually localized vibrational modes for complicated cases.

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For cisplatin molecule, we used C2v type Pulay coordinates for Pt square planar structure 8


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about 40◦ (N1) and 20◦ (N2) with respect to the gas phase structure (Fig. 2 inset) and

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form asymmetric intermolecular HBs with neighbouring molecules (Fig. 2). We noted that

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although the detailed orientation and the strength of HBs may depend on the exchange-

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correlation functional used in the DFT calculations as well as by the difference of lattice

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constants reported in the low- and the high-resolution X-ray crystal structures, the observed

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asymmetric hydrogen bonding environment in solid phase is a general feature. This is also

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supported by the high-resolution X-ray crystal structure of cisplatin where positions of hy-

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drogen atoms were resolved from neutron powder diffraction. 49 Table 1: Comparison of the calculated and experimental bond lengths (Å) and bond angles(◦ ) of cisplatin.

r(P t − N 1) r(P t − N 2) r(P t − Cl1) r(P t − Cl2) 6 (N 1P tCl1) 6 (N 2P tCl2) 6 (N 1P tN 2) 6 (Cl1P tCl2)

gas 2.08 v.s. 2.31 v.s 82.3 v.s 99.7 95.8

Calc. solid 2.038 2.043 2.362 2.363 89.1 87.9 91.3 91.6

aqueous 2.04(4) v.s. 2.36(5) v.s 91(4) v.s. 85(3) 91(3)

Exp. 48 solid 2.05(4) 1.95(4) 2.328(9) 2.333(9) 92(1) 88.5(0.9) 87(2) 91.9(0.4)

Exp. 49 solid 2.049(3) 2.047(3) 2.3206(3) 2.3216(8) 89.18(9) 88.55(9) 90.62(12) 91.65(3)

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For the vibrational properties, the full list of 27 normal frequencies of cisplatin in solid

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phase and gas phase is reported in Table 2. We were aware that the cutoff for plane wave

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basis sets and the choice of the exchange-correlation functional are important factors for

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an accurate determination of vibrational frequencies. For instance, it is known that the

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inclusion of Hartree-Fock exchange leads to a significant improvement on the calculated

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vibrational spectra. 67 Regarding to this issue, we found that adopting a cutoff at 100 Ry

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in gas phase calculations does not change the normal modes themselves compared to the

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results using a cutoff at 70 Ry but slightly shifts the frequencies with no general tendency

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(Table 2). As shown in Table 2, the calculated normal frequencies in solid phase are in good

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agreement with the ones resolved from Raman spectroscopy under the same conditions. 25

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This suggests that i) the level of theory used here is sufficient for describing the vibrational 10


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properties of cisplatin molecule; ii) The anharmonicity, which usually leads to the red-shift

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of the frequency, plays a less significant role in the case of cisplatin molecule, in particular

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for high wavenumber modes. Moreover, throughout this work, choices of cutoff and the

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exchange-correlation functional were the same in gas phase, solid phase and aqueous solution

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calculations. The following results and conclusions will mainly concern spectral differences

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between gas phase and condensed phases, therefore we expect a further benefit due to error

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cancellation.

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In solid phase, it is found that N−H stretching modes of cisplatin molecule (ν22 to ν27

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in Table 2) are generally red-shifted with respect to gas phase. Since both calculations were

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done with the harmonic approximation, forming of intermolecular HBs in solid phase is the

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only reason for this red-shift. In addition, we found that stretching modes ν22 ↔ ν23 , ν24 ↔

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ν25 ν26 ↔ ν27 become non-degenerate in frequency in contrast to that in gas phase. Certainly,

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this comes from the fact that two ammonia groups form asymmetric number/strength of HBs

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and the gas phase C2v symmetry of cisplatin molecules is broken in solid phase.

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In terms of normal modes, it is found that Pt−N stretching modes (ν10 and ν11 ) are

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decoupled and localized to individual Pt-N bonds, at variance with what was obtained in

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gas phase, in which they distribute equally to each bond (Fig. 3). A similar pattern is found

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also in Pt−Cl stretching modes (ν8 and ν9 ). Interestingly, the decoupling and localization of

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Pt−N and Pt−Cl stretching modes of cisplatin in solid phase resembles that of O−H stretch-

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ing modes of water molecules in water dimer and liquid water. 68 As revealed previously, this

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phenomenon comes from the broken symmetry of the target molecules in asymmetric hydro-

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gen bonding environment. 68 Moreover, it is worth to note that the degree of the decoupling

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and localization indeed provides a way to gauge the details of HBs asymmetry.

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In literature, the low frequency modes (ν1 to ν7 ) of cisplatin in solid phase were seldom

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addressed, 19,20,24,25 probably because they are mostly Raman or IR inactive. It is found

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that: 1) Modes δCl−P t−Cl and δN −P t−N are both blue-shifted (150 cm−1 → 161 cm−1 and 255

225

cm−1 → 290 cm−1 respectively). This is in agreement with the fact that angles of Cl−Pt−Cl

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Gas Solid Aqueous a 25 Mode # Fundamental IR Raman Sym. BP/PW BPW91/LanLDZ BP/PW Exp. Pulay (n=2) 1 ρ′ a2 108(113) 111 186 163 2 δCl−P t−Cl Y a1 150(149) 135 161 162 155 3 ρ Y b1 151(165) 154 217 171 4 τN′ H3 Y b1 154(154) 157 263* 143* 5 τN H3 a2 136(148) 159 246* 140* 6 δN −P t−Cl Y b2 233(235) 228 224 210 184 7 δN −P t−N Y Y a1 255(249) 227 290 255 250 ′ 8 νP t−Cl Y Y b2 333(334) 318 304* 317 319* 9 νP t−Cl Y Y a1 345(345) 328 309* 323 348* Y Y b2 442(450) 469 512* 508 538* 10 νP′ t−N 11 νP t−N Y Y a1 479(480) 472 542* 524 550* ′ 12 θN H3 Y a2 690(701) 759 800* 724 795* 13 θN H3 Y Y b1 707(718) 777 830* 789 802* ′ 14 θN Y Y b 741(746) 811 838* 811 808* 2 H3 15 θN H3 Y Y a1 761(767) 843 865* 824 817* 16 δ N H3 Y Y b2 1195(1206) 1252 1272* 1295 1299* 17 δ N H3 Y Y a1 1202(1217) 1255 1318* 1316 1338* ′ 18 δ N H3 Y Y b2 1565(1576) 1631 1558* 1537 1595* ′ 19 δN Y Y a 1567(1580) 1639 1567* — 1597* 1 H3 ′ Y a2 1588(1602) 1663 1598* 1601 1602* 20 δ N H3 ′ 21 δ N H3 Y Y b1 1591(1608) 1668 1620* 1648 1612* 22 νN −H Y Y a1 3200(3214) 3228 3198* 3211 3214*# ′ 23 νN −H Y Y b2 3201(3216) 3228 3217* — 3237*# 24 νN′ −H Y Y b2 3365(3387) 3441 3274* 3287 3284*# 25 νN −H Y Y a1 3366(3388) 3442 3287* — 3290*# ′ Y a2 3419(3444) 3518 3306* 3309 3318*# 26 νN −H 27 νN −H Y Y b1 3420(3445) 3519 3350* — 3321*# ′ ′ Note: ν and ν (bond symmetric and asymmetric stretch), δ (bend or symmetric deformation), δ (degenerative deformation), θ and θ′ (in-phase and out-of-phase rock), τ and τ ′ (in-phase and out-of-phase twist), ρ and ρ′ (skeletal in-phase and out-of-phase deformation).*: Decoupled and localized modes (see Text for discussions). #: These modes are subject to a spurious red-shift because of the fictitious mass used in Car-Parrinello MD (see Text for discussions). For gas phase, the symmetries of the modes are also shown, where there are 5 belonged to a2 symmetry which are IR inactive. All the modes were sorted ascendingly in frequency with respect to the gas phase BPW91/LanLDZ calculation. Number in parenthesis calculated with using and increased plane wave cutoff of 100 Ry.

Table 2: The comparisons of normal frequencies of cisplatin molecule in gas phase, crystal and aqueous solution.

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240


wavenumber smaller than 2000 cm−1 (see Fig. S2 in Supporting Information).

241

Interestingly, we found that the first group of N-H stretching modes (ν22 and ν23 in

242

Table 2) have a blue-shift of 120 cm−1 in aqueous solution with respect to gas phase at 20K.

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This leads to a reduction of about 70 cm−1 of the frequency gab between the first group

244

(ν22 and ν23 in Table 2) and the second group (ν24 and ν25 in Table 2) of N-H stretching

245

modes, with respect the gas phase value of 160 cm−1 . Such unexpected blue-shift has to

246

be associated with intermolecular HBs between chlorine and hydrogen atoms. It is found

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that the Cl-H distance of cisplatin molecules in gas phase at 0K and 20K has two distinct

248

populations with ratio 1:2 (Fig. 4). Temperature effect alone help the rotation of NH3 group

249

and modulate the ratio between two populations. However, intramolecular HBs are strong

250

enough, therefore two populations remain distinct from each other. Only in the aqueous

251

solution, water molecules help to lower the rotational barrier of NH3 groups and to decrease

252

the strength of Cl-H HBs. It suggests that NH3 groups of cisplatin in aqueous solution

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resemble the ammonia in gas phase with C3v symmetry. This consequently leads to the

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observed blue-shift of the first group of N-H stretching modes (ν22 and ν23 ) and breaks the

255

gas phase C2v symmetry of cisplatin molecules in aqueous solution. It is worth to note

256

that these observations come from the VDOS of MD simulations and do not depend on the

257

procedure of the effective normal modes analysis.

258

Indeed, the blue-shift of the symmetric N-H stretching modes (ν22 and ν23 ) also appears

259

in solid phase. Experimental spectroscopy in solid phase reports that frequency gap between

260

the first group (ν22 and ν23 in Table 2) and the second group (ν24 and ν25 in Table 2) of

261

N-H stretching modes is reduced up to 76 cm−1 , 25 which is very close to the one calculated

262

in aqueous solution (70 cm−1 ). Considering that the calculated average bond distances and

263

angles of cisplatin in aqueous solution are very close to those reported in X-ray crystal struc-

264

ture (Table 1), it would not be surprising to see this spectral feature in both aqueous solution

265

and solid phase. Although a direct quantitative comparison cannot be done, we found the

266

calculated IR and Raman spectra of cisplatin in aqueous solution are in general agreement

15




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294

neutron scattering study of cisplatin in solid phase assigned such splitting to be 28 cm−1 , 70

295

which can not be reproduced by gas phase calculations. On the contrary, our calculated IR

296

spectrum from time-correlation functional formalism fairly reproduces such splitting of NH3

297

symmetric deformation modes (Fig. 7).

298

It should be pointed out that in the long-time limit, the average Hessian and therefore

299

the normal modes of cisplatin in aqueous solution have C2v symmetry. However, in cases

300

where the environment is fluctuating between different conformations, the effective normal

301

modes analysis based on VDOS and the average Hessian analysis give different results. It has

302

to be considered that because of this fluctuating environment, the cisplatin in the condensed

303

phase does not have C2v symmetry anytime, although on average it has C2v symmetry.

304

This is indeed our case, since water is prevalently binding to one of the two NH3 groups

305

at a certain time. Indeed, when looking into the corresponding effective normal modes in

306

aqueous solution (Fig. 7 inset), it is found that the C2v symmetry is broken and modes are

307

decoupled and localized.

308

As demonstrated by the effective normal modes analysis in the case of liquid water, the

309

instantaneous asymmetric hydrogen bonding environment would lead to a frequency sepa-

310

ration of O-H stretching modes in a non-trivial manner. 68 Correspondingly, the observed

311

frequency splitting of NH3 symmetric deformation modes comes from a similar origin. Such

312

a phenomenon is not present in gas phase but is present in both our VDOS analysis and

313

in the experimental data. Therefore, our relatively short simulation catches the underlay-

314

ing physical picture and provides a rationale, although a quantitative determination of the

315

relationship between the degree of environmental asymmetry and the frequency separation

316

of cisplatin would require a large sample of QM/MM MD simulations, which is out of the

317

scope of the present work.

19




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328

phase calculations and the X-ray crystal structure can be resolved by considering inter-

329

molecular HBs in the calculations of periodic crystal structure. In addition, our simulations

330

in condenses phase show that asymmetric environmental effects lead to the blue-shift in the

331

N-H stretching region and the frequency splitting of NH3 symmetric deformation modes.

332

Subsequently, it provides a physical explanation for these spectral features as observed in

333

experiments, which can not be revealed by gas phase calculations alone.

334

Furthermore, we noticed that the decoupling and localization of several vibrational modes

335

of cisplatin founded here in solid phase and aqueous solution, such as Pt-N and Pt-Cl stretch-

336

ing modes, resembles those of O−H stretching modes of water molecules in water dimer and

337

liquid water. 68,71 Because of the same gas phase C2v molecular symmetry for both cases,

338

we suggest that the decoupled and localized modes as well as the relationship between the

339

environmental asymmetry and the frequency separation could be a general characteristic for

340

this type of HBs forming molecules in condensed phases.

341

Acknowledgement

342

We gratefully acknowledge M. Martinez and D. Bovi for their assistance in the analysis of the

343

effective normal modes and W. Andreoni for providing us with the Platinum pseudopoten-

344

tial. C.Z. thanks for the interesting discussions on the instantaneous asymmetry with T. D.

345

Kühne and R. Z. Khaliullin. Computational resources were supplied by CASPUR, CINECA,

346

and the Caliban-HPC centre at the University of L’Aquila. C.Z. acknowledges the Gauss

347

Center for Supercomputing (GCS) for providing computing time through the John von Neu-

348

mann Institute for Computing (NIC) on the GCS share of the supercomputer JUQUEEN at

349

Jülich Supercomputing Center (JSC). L.G. acknowledges funding provided by the European

350

Research Council project n. 240624.

351

Supporting Information Available

352

Supporting information includes: A) The effects on C3v Pulay coordinates in effective normal 21



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Page 22 of 30

353

modes analysis of cisplatin. B) The convergence issue of VDOS of cisplatin in aqueous

354

solution; C) The effects of fictitious mass in Car-Parrinello MD on the vibrational spectra of

355

cisplatin; C) The residence time of water molecules around NH3 groups of cisplatin.

356

material is available free of charge via the Internet at http://pubs.acs.org/.

357

References

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365

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