This research is supported by the National Key Research and Development Program of China (2017YFA0206801, 2018YFA0208600), Natural Science Foundation of Jiangsu Province,&#160;and National Natural Science Foundation of China (91645116). L.X is the Zhong-Wu Specially Appointed Professor of the Jiangsu University of Technology. The authors acknowledge the suggestions from Dr. Hao Hu and Dr. Mingjun Yang.

1. Building model
<ol>
	<li>Build porphycene structure: Open GaussView software by double-click the mouse. Then click Element Fragment button in the menu of the GaussView to choose the needed elements. Construct porphycene. Then click File button to save as the pdb file.</li>
	<li>Solvate the model: Solvate porphycene in a cubic TIP3P21 water box with an edge length of 38 &#197;...

<ol>
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L. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Comparison+of+simple+potential+functions+for+simulating+liquid+water.">Comparison of simple potential functions for simulating liquid water.</a> The Journal of Chemical Physics. 79 (2), 926-935 (1983).</li><li>Walewski, L., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Scc-dftb+energy+barriers+for+single+and+double+proton+transfer+processes+in+the+model+molecular+systems+malonaldehyde+and+porphycene.">Scc-dftb energy barriers for single and double proton transfer processes in the model molecular systems malonaldehyde and porphycene.</a> International Journal of Quantum Chemistry. 106 (3), 636-640 (2006).</li><li>Bakowies, D., Thiel, W. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Hybrid+models+for+combined+quantum+mechanical+and+molecular+mechanical+approaches.">Hybrid models for combined quantum mechanical and molecular mechanical approaches.</a> The Journal of Physical Chemistry. 100 (25), 10580-10594 (1996).</li><li>Hu, H., Yang, W. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Development+and+application+of+ab+initio+QM/MM+methods+for+mechanistic+simulation+of+reactions+in+solution+and+in+enzymes.">Development and application of ab initio QM/MM methods for mechanistic simulation of reactions in solution and in enzymes.</a> Journal of Molecular Structure: THEOCHEM. 898 (1-3), 17-30 (2009).</li><li>Xie, L., Yang, M., Chen, Z. 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The authors have nothing to disclose.

The structure of porphycene was shown in Figure 1. The electrostatic embedding QM/MM hybrid potential with SITS method was used to describe the chemical reactions in water23,24. The proton transfer occurs within porphycene3 and thus porphycene is set as QM region and the reminding water is set as MM region. Herein we adopted DFTB/MIO as our QM method to treat the porphycene by balancing the efficiency and accu...

The proton transfer process in porphycenes holds potential applications in developing molecular switches, transistors and information storage devices1,2. In particular, tautomerization in porphycenes through double proton transfer process has attracted wide interest in the fields of spectroscopy and photophysics2. The inner hydrogen atoms of porphycene can migrate from one trans isomer to the other equivalent trans isomer through double proton transfer process as shown in Figure 1. Two mechanisms have been proposed for the double proton transfer process: the concerted and the stepwise mechanism3,4. In the concerted double proton transfer process, both proton atoms move to the transition state synchronously in a symmetric way, whereas one proton completes the transfer before the other proton in a stepwise process. Two hydrogen atoms can transfer simultaneously or stepwise depending on the correlation strength between two hydrogen atoms5.
Isotopic substitution has been used to detect the structural properties of molecules and rate constants of reaction kinetics6. Single deuterium substitution in the inner hydrogen of porphycene leads to an asymmetric shape of the molecule. The hydrogen bond may expand or contract because of mass difference between the hydrogen and deuterium atoms. The isotopic substitution introduces a perturbation in the scaffold of porphycene. The question arises that whether asymmetric structure would affect the proton transfer process. Limbach and coworkers reported that the replacement of hydrogen with deuterium will compress both hydrogen bonds, and the cooperative coupling of two hydrogen bonds in porphycene may favor concerted mechanism7, whereas Yoshikawa stated the deuteration would make the stepwise mechanism contribute more than the concerted mechanism8. Experimental techniques, such as force spectroscopy, have been developed to capture tautomerization details in a single porphycene9. However, it is still challenging to determine the atomic details of proton transfer experimentally because of its transient nature.
Theoretical calculations and simulations can act as complementary tools in elucidating the reaction mechanisms of proton transfer. Among different theoretical methods, molecular dynamics (MD) simulations can monitor dynamic motions of each atom, and has been widely used to reveal complex mechanisms in chemical and enzymatic reactions. However, regular MD simulations tend to suffer from insufficient sampling issue, especially when high energy barrier exists in the process of interest. Therefore, enhanced sampling methods have been developed, which include transition path sampling10,11, umbrella sampling (US)12,13, and integrated tempering sampling (ITS)14,15. Combination of different enhanced sampling methods can further increase sampling efficiency16,17,18. To harness the enhanced sampling algorithms in simulating chemical reactions, we have implemented the selective integrated tempering sampling (SITS) method with quantum mechanical and molecular mechanical (QM/MM) potentials recently19. The proposed SITS-QM/MM method combines the advantages from both methods: the SITS method accelerates the sampling and can explore all possible reaction channels without prior knowledge of the reaction mechanism, and QM/MM provides more accurate description of the bond forming and bond breaking process, which cannot be simulated by MM methods solely. The implemented SITS-QM/MM approach has successfully uncovered concerted double proton transfer, uncorrelated and correlated stepwise double proton transfer mechanism in different systems, without pre-defining reaction coordinates19. For porphycene, the stepwise but correlated proton transfer character has been reported19. The hybrid SITS-QM/MM method was used to investigate the isotopic effect in porphycene in our study, and below are the detailed descriptions of the algorithm and protocol of our method.
We have implemented SITS method with hybrid QM/MM potentials. The effective potential of SITS was defined to include the potential energy at different temperatures with the weighting factors nk to cover wider temperature ranges,
<img alt="Equation 1" src="/files/ftp_upload/60040/60040equ01.jpg" />
where, N is the number of canonical terms, &#946;k is the inverse temperature, and nk is the corresponding weighting factor for each canonical component. UE(R) and&#160;UN(R) represent the enhanced and non-enhanced terms in SITS and are defined as,
<img alt="Equation 2" src="/files/ftp_upload/60040/60040equ02.jpg" />
Us, Use and Ue are the potential energy of sub-system, the interaction between sub-system and the environment, and the potential energy of environment. QM/MM potential is expressed as a hybrid summation of three components,
<img alt="Equation 3" src="/files/ftp_upload/60040/60040equ03.jpg" />
where Uqm, Uqm/mm, and&#160;Umm are the internal energy term of the QM subsystem, the interaction energy between the QM and MM regions, and the interaction energy within the MM subsystem, respectively. The&#160;Uqm/mm term can be further divided into three components, which include the electrostatic, van der Waals, and covalent interaction energy terms between the QM and MM atoms,
<img alt="Equation 4" src="/files/ftp_upload/60040/60040equ04.jpg" />
We assign <img alt="Equation 5" src="/files/ftp_upload/60040/60040equ05.jpg" />, and <img alt="Equation 6" src="/files/ftp_upload/60040/60040equ06.jpg" /> into one&#160;Us term in SITS,
<img alt="Equation 7" src="/files/ftp_upload/60040/60040equ07.jpg" />
The full potential of the system was then decomposed into the energy of subsystem Us, the interaction energy between the subsystem and the environment Use, and the energy of environment Ue. For instance, in the system of the present work, the subsystem is the porphycence, and the environment the water.
The PMF profile along a collective variable&#160;&#964;(R) is derived as,
<img alt="Equation 8" src="/files/ftp_upload/60040/60040equ08.jpg" />
The generally used reaction coordinates for each hydrogen transfer of N1&#8722;H1&#183;&#183;&#183; N2 are q1 = (r1&#8722;r2)/2 and q2 = r1 + r2, where r1 is the distance of N1-H1 and r2 is the distance of H1-N2.
The method has been implemented in the QM/MM MD simulation package QM4D20. The complete source code and documentation can be found here: http://www.qm4d.info/.
Generally, the SITS-QM/MM MD simulations involve four steps: pre-equilibrium (pre-sits); optimization nk (opt-sits); production simulation and data analysis.

<table>
	<tbody>
		<tr>
			<td>operating system</td>
			<td>CentOS Linux release 6.0</td>
			<td></td>
			<td></td>
		</tr>
		<tr>
			<td>QM4D software</td>
			<td>http://www.qm4d.info/</td>
			<td></td>
			<td>in-house program</td>
		</tr>
		<tr>
			<td>Computer desktop</td>
			<td>HP</td>
			<td></td>
			<td></td>
		</tr>
	</tbody>
</table>

isotopic effect in double proton transfer process of porphycene investigated by enhanced qm/mm method

The single deuterium substitution in porphycene leads to an asymmetric molecular geometry, which may affect the double proton transfer process in the porphycene molecule. In this study, we applied an enhanced QM/MM method called SITS-QM/MM to investigate hydrogen/deuterium (H/D) isotope effects on the double proton transfer in porphycene. Distance changes in SITS-QM/MM molecular dynamics simulations suggested that the deuterium substituted porphycene adopted the stepwise double proton transfer mechanism. The structural analysis and the free energy shifts of double proton transfer process indicated that the asymmetric isotopic substitution subtly compressed the covalent hydrogen bonds and may alter the original transition state location.

The single deuterium substitution effect on double proton transfer process in porphycene was examined in the current protocol (Figure 1). The potential energy of QM sub-system and the water during pre-equilibrium and optimization step were checked to make sure the energy has been broadened to a wider energy range (Figure 2). The representative distance and angle changes (Figure 3 and Figure 4), and the ...

Watch this Scientific Journal Video about Isotopic Effect in Double Proton Transfer Process of Porphycene Investigated by Enhanced QM/MM Method at JoVE.com

Isotopic Effect in Double Proton Transfer Process of Porphycene Investigated by Enhanced QM/MM Method

A protocol that uses enhanced QM/MM method to investigate the isotopic effect on the double proton transfer process in porphycene is presented here.

The single deuterium substitution in porphycene leads to an asymmetric molecular geometry, which may affect the double proton transfer process in the ...

A Enhanced QM/MM Method overcomes simple issues in normal QM/MM simulation. The Six QM/MM Method accelerates select assembly for the QM region, and can capture the chemical reaction pathways result in defining reaction coordinate. With this protocol, we successfully captured a chemical reaction pathways of double proton transfer and a reveal a deuterium substitution effect on a transfer mechanism of provency in water.The protocol can be used to explore halogen or our deuterium substitution in heat identification in drug discovery. The main advantage of Six QM/MM Method is that, we don't need it to define brine reaction coordinate or introduce an device for chemical reaction pathway when exploring reaction mechanism. enable us to identify possible reaction pathways that in from react.The method that can be used and extended to a high level QM Method and it could become a important tool to investigate the reaction mechanism for chemical reaction in solution. To begin this procedure, initiate the presets by setting runtype as 100, temp0 as 300, templow as 260, temphigh as 1300, and step as 120, 000 in the input file. Then, issue the appropriate command as shown here.During the preset stage, monitor the energy of each term to calculate the mean values. Use the grep Linux commands to extract the energy. To modify the average energies in the md-input file, calculate the average energies based on the output of the previous command line, and to modify the v-shift line in the input file with the newly generated averages.Initiate offsets in the QM4D program by typing the command to start the optimization step. Next, plug the energy propagation with the grace program, and make sure the energy fluctuation can cover the lowest and the highest ends of the temperature range. After optimization, save the final nk values of the offset step into a new file which is named nk.dat in this protocol. To prepare the md-input file, set the runtype as one in the new input file to start the production simulations step. Specify the file name with the stored nk file as nkfile nk.dat in the input file. The number of time steps was set as 6, 400, 000 in the present systems. The simulation counter is system dependent so change the simulation stat based on your specific demand.Select a proper number of time step to use for marginal transition between different states for your own system. Initial the production in these simulation, by issuing the appropriate command to start MD Simulations. To monitor the bond forming and breaking process during the production phase, use the grep command to check the distance changes of H1N1 and H1N2 along the simulation time.The same operation can be conducted for H2N3 and H2N4. Then, plug the distance propagation using the accumulated distance value during the production's simulations. Extract the reaction coordinates, and the energy terms from the production output file generated by QM4D by grep command.Organize the data in four columns, and write them into the data file at each timeframe. Calculate the free energy by issuing the appropriate command. Finally, to project the free energy on the two-dimensional landscape, type the appropriate command.The single deuterium substitution effect on double proton transfer process in porphycene was examined in the current protocol. The potential energy of the QM subsystem, and the water during the pre-equilibrium and optimization steps were checked to make sure the energy of the QM region had been broadened to a wider energy range, without effecting the energy of the environment. The representative distance and angle changes, and the projected free energy changes were used to characterize the deuterium substitution effect on the geometry and proton transfer process of porphycene.The Six QM/MM Method achieves enhanced assembly in the energy space. The specified merger range should achieve broadened energy distribution. This method not only capture the top of reaction channel you got can transfer, but it also has a potential of identifying reaction products from norm reaction states result from reaction mechanism.This protocol acts as a starting point to investigate the chemical reaction mechanisms in a condensed environment. Higher level QM methods can be readily combined with the Six QM/MM Method to explore more complex systems in the future.

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Chemistry

6.1K Görüntüleme.  Chinese Academy of Sciences. Geliştirilmiş QM/MM Yöntemi, normal QM/MM simülasyonundaki basit sorunların üstesinden gelinir. Altı QM/MM Yöntemi QM bölgesi için seçilmiş montajı hızlandırır ve kimyasal reaksiyon yollarını yakalayarak reaksiyon koordinatını tanımlar. Bu protokolle, çift proton transferinin kimyasal reaksiyon yollarını başarıyla yakaladık ve suda kanıtlanmışlığın transfer mekanizması üzerinde döteryum ikame etkisi ortaya çıkartın.Protokol, ilaç keşfinde ısı ...