exercises:2015_cecam_tutorial:urea
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exercises:2015_cecam_tutorial:urea [2015/08/19 13:16] – created tmueller | exercises:2015_cecam_tutorial:urea [2020/08/21 10:15] (current) – external edit 127.0.0.1 | ||
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+ | ====== QM/MM study of UREA Zwitterion in water ====== | ||
+ | |||
Problem: QM/MM study of the Urea Zwitterion in water by means of a QM/MM Hamiltonian. | Problem: QM/MM study of the Urea Zwitterion in water by means of a QM/MM Hamiltonian. | ||
- | For this tutorial some input and output files are given in order to present a complete procedure to solve the given problem. Some hints are also given to help in the analysis of the results. In order to be able to run these examples, some paths need to be correctly set in the input files (i.e. set the variables ROOT for instance). | + | * Original author: Marcella Iannuzzi |
+ | * Complete source and output files: [[http:// | ||
+ | |||
+ | ===== Introduction ===== | ||
+ | |||
+ | For this tutorial some input and output files are given in order to present a complete procedure to solve the given problem. Some hints are also given to help in the analysis of the results. In order to be able to run these examples, some paths need to be correctly set in the input files (i.e. set the variables | ||
In this tutorial exercise, we will cover several theoretical aspects covered during the lectures: | In this tutorial exercise, we will cover several theoretical aspects covered during the lectures: | ||
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* Metadynamics | * Metadynamics | ||
- | In order to have a reasonable QM/MM starting structure, we need to prepare a fully functional classical setup. In order to do so, we need to prepare a classical force field for both UREA (Zwitterionic form) and water. In this tutorial we will not cover specifically this aspect, which has been fulfilled using the ambertools (http:%%//%%ambermd.org/). For people willing to understand and dominate these operative procedures, the link provided above contains tons of information. For your convenience, | + | In order to have a reasonable QM/MM starting structure, we need to prepare a fully functional classical setup. In order to do so, we need to prepare a classical force field for both UREA (Zwitterionic form) and water. In this tutorial we will not cover specifically this aspect, which has been fulfilled using the [[http:// |
The main UREA example distribution contains the following directories: | The main UREA example distribution contains the following directories: | ||
- | * **Files** contains FORCE_EVAL and topology/ | + | * '' |
- | + | * '' | |
- | * **Prepare_Molecules** contains all files relevant to the creation of the force field for UREA zwitterion and water using the ambertools\\ | + | * '' |
- | + | * '' | |
- | * **Prepare_Solvated_Box** Contains files and setup to prepare a box of water solvating the UREA zwitterion\\ | + | * '' |
- | + | * '' | |
- | * **RUN01_EQUIL_MM** contains classical NPT equilibration\\ | + | * '' |
- | + | * '' | |
- | * **RUN01_EQUIL_MM_AVG** contains classical NVT equilibration upon averaging the box from the previous run\\ | + | |
- | + | ||
- | * **RUN01_EQUIL_QMMM** contains QM/MM NVT equilibration\\ | + | |
- | + | ||
- | * **RUN02_QMMM_MTD1** contains the sampling (by means of metadynamics) of the reaction from Zwitterionic to neutral form\\ | + | |
- | + | ||
- | * **RUN02_QMMM_MTD2** contains the sampling (by means of metadynamics) of the elimination reaction: i.e. elimination of NH$_3$ | + | |
The tasks we will complete in this tutorial exercise are: | The tasks we will complete in this tutorial exercise are: | ||
- | * We will equilibrate the simulation box by means of classical Hamiltonian employing an NPT ensemble\\ | + | * We will equilibrate the simulation box by means of classical Hamiltonian employing an NPT ensemble |
- | + | * Based on the averages of the NPT we will equilibrate at the NVT level with an average simulation box | |
- | * Based on the averages of the NPT we will equilibrate at the NVT level with an average simulation box\\ | + | |
* One the system is equilibrated at the classical Hamiltonian level we will switch to a QM/MM Hamiltonian, | * One the system is equilibrated at the classical Hamiltonian level we will switch to a QM/MM Hamiltonian, | ||
- | * Study the chemical reactivity of the Zwitterion in solution: by inspecting the possibility of having a reversal reaction with formation of neutral urea or alternatively the elimination reaction, with formation of NH$_3$ | + | * Study the chemical reactivity of the Zwitterion in solution: by inspecting the possibility of having a reversal reaction with formation of neutral urea or alternatively the elimination reaction, with formation of < |
- | ====== Theoretical Background | + | ===== Theoretical Background ===== |
Urea is formed in large quantities as a product of catabolism of nitrogen-containing compounds. Owing to its resonance stabilization, | Urea is formed in large quantities as a product of catabolism of nitrogen-containing compounds. Owing to its resonance stabilization, | ||
- | Cyanate ion further readily undergoes conversion to CO2 and ammonia. In contrast, when catalyzed by ureases, urea is generally believed to undergo hydrolysis rather then ammonia elimination producing either HCO3- and NH4+ or ammonium carbamate, depending on the buffer system. Activation energies for urea decomposition in water at different pH have been obtained experimentally. For neutral pH, the reported activation energy ranges from 28.4 Kcal/mol to 32.4 Kcal/mol. There have been also numerous theoretical investigations of the decomposition of urea and related systems. In all of them the explicit representation of the solvent was found to be essential for detailed resolution of the mechanism, identification of the rate determining step and evaluation of the barrier. In particular in a very recent paper by Jorgensen et al. the hydrogen bonded water molecules were found to act as hydrogen shuttle for the first step of the elimination reaction. The forming zwitterionic intermediate, | + | Cyanate ion further readily undergoes conversion to < |
- | The goal of this exercise will be to inspect the chemical reactivity of the zwitterion surrounded by water molecules. In this exercise, in a very simplicistic way, only urea will be considered QM while the rest of the system will be described with a classical Hamiltonian. By some high level calculations, | + | The goal of this exercise will be to inspect the chemical reactivity of the zwitterion surrounded by water molecules. In this exercise, in a very simplicistic way, only urea will be considered QM while the rest of the system will be described with a classical Hamiltonian. By some high level calculations, |
- | ====== First task: MM isobaric/ | + | ===== First task: MM isobaric/ |
The first task to complete is the NPT equilibration of the entire system (UREA+water) with a classical force-field. In principle, one could start, for very difficult molecular cases hard to parametrize, | The first task to complete is the NPT equilibration of the entire system (UREA+water) with a classical force-field. In principle, one could start, for very difficult molecular cases hard to parametrize, | ||
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The force-field, | The force-field, | ||
- | In the directory Files, you will find two files '' | + | In the directory |
- | The classical equilibration is performed in the directory RUN01_EQUIL_MM.Let’s have a look more in details at the input file used to perform the NPT equilibration. | + | The classical equilibration is performed in the directory |
In the SUBSYS section the information on the structure and the simulation box are specified as: | In the SUBSYS section the information on the structure and the simulation box are specified as: | ||
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&END CELL | &END CELL | ||
& | & | ||
- | CONN_FILE_NAME | + | CONN_FILE_NAME ${ROOT}/ |
CONNECTIVITY AMBER | CONNECTIVITY AMBER | ||
- | COORD_FILE_NAME | + | COORD_FILE_NAME ${ROOT}/ |
COORDINATE CRD | COORDINATE CRD | ||
&END TOPOLOGY | &END TOPOLOGY | ||
&END SUBSYS | &END SUBSYS | ||
</ | </ | ||
- | The initial cell size was provided by LEAP and in the topology we specify both the starting coordinates '' | + | The initial cell size was provided by LEAP and in the topology we specify both the starting coordinates '' |
We run the optimization at the MM level with the following setup: | We run the optimization at the MM level with the following setup: | ||
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&MM | &MM | ||
& | & | ||
- | parm_file_name | + | parm_file_name ${ROOT}/ |
parmtype AMBER | parmtype AMBER | ||
&spline | &spline | ||
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&END | &END | ||
</ | </ | ||
- | In the FORCE_FIELD | + | In the '' |
- | The core of the evaluation in a classical run, is the evaluation of the electrostatic. We can adjust these parameters in the &POISSON section (similarly to the DFT calculations). For classical runs we can employ either standard EWALD summations, Particle-Mesh Ewald (PME) sums or Smooth-Particle-Mesh Ewald ones (SPME). | + | The core of the evaluation in a classical run, is the evaluation of the electrostatic. We can adjust these parameters in the '' |
For this exercise we emply the SPME with a grid mesh of 54 for all 3 dimensions and the $\alpha$ parameter for the reciprocal space contributions is equal to 0.4. | For this exercise we emply the SPME with a grid mesh of 54 for all 3 dimensions and the $\alpha$ parameter for the reciprocal space contributions is equal to 0.4. | ||
- | The control of the NPT equilibration is specified instead by the MD section: | + | The control of the NPT equilibration is specified instead by the '' |
< | < | ||
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It is important to notice as well the output frequency of files and other additional information, | It is important to notice as well the output frequency of files and other additional information, | ||
- | At this level you can launch the run: for the provided setup it takes almost 5:00 hours on a single processor (3 GHz). Upon completion of the equilibration we need to inspect whether 50 ps where enough to equilibrate the system. Check the convergence of the cell parameters, by simply plotting (gnuplot or your preference plot manager) the content of the file '' | + | At this level you can launch the run: for the provided setup it takes almost 5:00 hours on a single processor (3 GHz). Upon completion of the equilibration we need to inspect whether 50 ps where enough to equilibrate the system. Check the convergence of the cell parameters, by simply plotting (gnuplot or your preference plot manager) the content of the file '' |
- | ====== Second task: MM isothermal ensemble | + | ===== Second task: MM isothermal ensemble ===== |
- | Using the average parameters of the cell lattice, as determined in the previous run, we setup an input file to run an NVT equilibration, | + | Using the average parameters of the cell lattice, as determined in the previous run, we setup an input file to run an NVT equilibration, |
< | < | ||
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& | & | ||
- | RESTART_FILE_NAME ../ | + | RESTART_FILE_NAME ../ |
RESTART_CELL F | RESTART_CELL F | ||
&END | &END | ||
</ | </ | ||
- | All the files generated in this task can be found in the directory RUN01_EQUIL_MM_AVG. For the purpose of equilibrating the system in the NVT ensemble we will run 5 ps. Check the '' | + | All the files generated in this task can be found in the directory |
- | ====== Third task: QM/MM isothermal ensemble | + | ===== Third task: QM/MM isothermal ensemble ===== |
- | Starting from the MM system, equilibrated at the right pressure and temperature, | + | Starting from the MM system, equilibrated at the right pressure and temperature, |
- | All the informations about a QM/MM run are specified in the QMMM section being part of the FORCE_EVAL%QMMM. In particular, we need to specify first the QM CELL. This is mandatory and important for DFT calculations (performance, | + | All the informations about a QM/MM run are specified in the QMMM section being part of the '' |
< | < | ||
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For this specific example, we need also to introduce an additional modification in the force-field. In fact, in the classical force-field, | For this specific example, we need also to introduce an additional modification in the force-field. In fact, in the classical force-field, | ||
- | We can do that with an additional FORCEFIELD section inside the QMMM one: | + | We can do that with an additional |
< | < | ||
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No other modification are necessary to perform this task. Run the MD equilibration and inspect the temperature, | No other modification are necessary to perform this task. Run the MD equilibration and inspect the temperature, | ||
- | ===== Homeworks | + | ==== Homeworks ==== |
- | Try to convert this input to use GPW. Hints: when setting-up a correct | + | Try to convert this input to use GPW. Hints: when setting-up a correct |
- | ====== Fourth task: QM/MM Metadyanamics simulations | + | ===== Fourth task: QM/MM Metadyanamics simulations ===== |
Startin from the equilibrated QM/MM system, we will perform two metadynamics run to inspect: | Startin from the equilibrated QM/MM system, we will perform two metadynamics run to inspect: | ||
- | * the reaction Zwitterionic-Neutral reaction in solution (in directory RUN02_QMMM_MTD1) | + | * the reaction Zwitterionic-Neutral reaction in solution (in directory |
- | * the elimination reaction, producing cyanic acid and ammonia (in directory RUN02_QMMM_MTD2) | + | * the elimination reaction, producing cyanic acid and ammonia (in directory |
- | ===== Zwitterion-Neutral mechanism | + | ==== Zwitterion-Neutral mechanism ==== |
In order to sample the reverse reaction, from Zwitterion to Neutral, we employ two collective variables, based on coordination: | In order to sample the reverse reaction, from Zwitterion to Neutral, we employ two collective variables, based on coordination: | ||
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&END METADYN | &END METADYN | ||
</ | </ | ||
- | Inspec the '' | + | Inspec the '' |
To determine the free energy profile employ the fes.sopt program. How deep is the basin? | To determine the free energy profile employ the fes.sopt program. How deep is the basin? | ||
- | ===== Elimination | + | ==== Elimination ==== |
- | The elimination reaction is sampled along the CV representing the bond between the NH$_3$ | + | The elimination reaction is sampled along the CV representing the bond between the < |
< | < | ||
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Similarly to the previous mechanism, inspect the COLVAR files, the trajectory and determine the barrier for the elimination process. | Similarly to the previous mechanism, inspect the COLVAR files, the trajectory and determine the barrier for the elimination process. | ||
- | ====== Questions | + | ===== Questions ===== |
- | Evaluate the free-energy for both processes: from Zwitterionic to Neutral form and for the elimination pathway. How do these numbers compare with the 5 kcal/mol predicted in several published works? Inspect carefully the metadynamics trajectory in order to find a solution (what is the first attempt of the hydrogen of NH3(+) before moving towards the NH(-) group? what would happen if the nearby water molecules would be treated QM?). | + | Evaluate the free-energy for both processes: from Zwitterionic to Neutral form and for the elimination pathway. How do these numbers compare with the 5 kcal/mol predicted in several published works? Inspect carefully the metadynamics trajectory in order to find a solution (what is the first attempt of the hydrogen of < |
- | ====== Homeworks | + | ===== Homeworks ===== |
Take into account a primary solvation shell of water molecules as a part of the QM subsystem, using a FLEXIBLE_PARTITIONING scheme to prevent the diffusion of the QM water molecules. Re-run the equilibration steps and perform the Zwitterionic-Neutral metadynamics. Do you see any change in the barrier energy? Why? | Take into account a primary solvation shell of water molecules as a part of the QM subsystem, using a FLEXIBLE_PARTITIONING scheme to prevent the diffusion of the QM water molecules. Re-run the equilibration steps and perform the Zwitterionic-Neutral metadynamics. Do you see any change in the barrier energy? Why? |
exercises/2015_cecam_tutorial/urea.1439990202.txt.gz · Last modified: 2020/08/21 10:14 (external edit)