exercises:2018_uzh_acpc2:prot_fol
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exercises:2018_uzh_acpc2:prot_fol [2018/05/17 01:59] – gtocci | exercises:2018_uzh_acpc2:prot_fol [2018/05/18 20:05] – [Task 1: Familiarize yourself] gtocci | ||
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====== Protein Folding in Solution ====== | ====== Protein Folding in Solution ====== | ||
- | In this exercise, you will calculate the protein folding free energy using thermodynamic integration, | + | In this exercise, you will calculate the protein folding free energy using thermodynamic integration, |
===== Background ===== | ===== Background ===== | ||
- | A model protein you will have to deal with is the alanine decapeptide. The folding/ | + | A model protein you will have to deal with is the alanine decapeptide. The folding/ |
\begin{equation} | \begin{equation} | ||
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===== Task 1: Familiarize yourself ===== | ===== Task 1: Familiarize yourself ===== | ||
- | Download the files: {{ :exercises:2017_uzh_acpc2:deca_ala.tar.gz |}} | + | Download the files: {{ :exercises:2018_uzh_acpc2:deca_ala_ex3.tar.gz |}} |
- | in the directory | + | in the directory |
'' | '' | ||
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'' | '' | ||
- | '' | + | '' |
'' | '' | ||
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===== Task 2: Perform constrained MD simulations ===== | ===== Task 2: Perform constrained MD simulations ===== | ||
- | To perform thermodynamic integration one has to run MD for different values of the distance between atoms 7 and 98, in each run it will be constrained. In the original file '' | + | To perform thermodynamic integration one has to run MD for different values of the distance between atoms 11 and 91, in each run it will be constrained. In the original file '' |
- | We have made this process automatic. To run TI for different values of the constraint, execute the script | + | We have made this process automatic. To run TI for different values of the constraint, execute the script |
<code - run_ti_jobs.sh > | <code - run_ti_jobs.sh > | ||
#!/bin/bash -l | #!/bin/bash -l | ||
for d in $(seq 16 1 20); do | for d in $(seq 16 1 20); do | ||
- | cp -r deca_ala $d | + | |
+ | | ||
cd $d | cd $d | ||
sed -e " | sed -e " | ||
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<note tip> | <note tip> | ||
* Be careful with the values chosen for the upper and lower bound of the constraints as the simulations might crash or the SHAKE algorithm for the computation of the constraints might not converge if the values of the constrained distances are unphysical. | * Be careful with the values chosen for the upper and lower bound of the constraints as the simulations might crash or the SHAKE algorithm for the computation of the constraints might not converge if the values of the constrained distances are unphysical. | ||
- | * We have set the number of step of each constrained MD to 200000, to get good statistics. Try to increase this number if you want to achieve better statistics or to decrease it to get the results faster, at the expense of a better | + | * We have set the number of steps of each constrained MD to 5000. Try to increase this number if you want to achieve better statistics or to decrease it to get the results faster, at the expense of a more converged free energy. |
</ | </ | ||
- | ==== Relevant constraint | + | ==== Relevant constraint |
+ | |||
+ | Look into the main input file of cp2k '' | ||
<code - constraint section> | <code - constraint section> | ||
& | & | ||
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COLVAR 1 | COLVAR 1 | ||
INTERMOLECULAR | INTERMOLECULAR | ||
- | TARGET [angstrom] | + | TARGET [angstrom] |
&END COLLECTIVE | &END COLLECTIVE | ||
& | & | ||
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&END | &END | ||
& | & | ||
+ | </ | ||
+ | |||
+ | <code - colvar section> | ||
+ | &COLVAR | ||
+ | & | ||
+ | ATOMS 11 91 | ||
+ | &END DISTANCE | ||
+ | &END | ||
</ | </ | ||
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- | * From these files you can calculate the average Lagrange multiplier of the Shake-algorithm like this: | + | * From these files you can calculate the average Lagrange multiplier of the Shake-algorithm |
< | < | ||
- | grep Shake yourprojectname.LagrangeMultLog | awk '{c++ ; s=s+$4}END{print s/c}' | + | grep Shake yourprojectname.LagrangeMultLog | awk '{c++ ; s=s+$4; sq=sq+$4*$4 }END{print s/c, sqrt(sq/c - s*s/ |
</ | </ | ||
- | * The average Lagrange multiplier is the average force $F(x)$ required to constrain the atoms at the distance $x$. | + | * The average Lagrange multiplier is the average force $F(x)$ required to constrain the atoms at the distance $x$. First of all, plot the force $F(x)$ with its standard error as a function of the collective variable to see if the simulation carried out so far is statistically relevant or the relative error is too large. |
- | * From these forces the free energy difference can be obtained via thermodynamic integration between the two states. Given that state $a$ and $b$ are the initial and the final values of the collective variable, extract the free energy difference from | + | * From the forces, the free energy difference can be obtained via thermodynamic integration between the two states. Given that state $a$ and $b$ are the initial and the final values of the collective variable, extract the free energy difference from |
\begin{equation} | \begin{equation} | ||
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\end{equation} | \end{equation} | ||
- | * Discuss the form of the free energy profile and comment on what is the most stable state of the protein. Is this result physical? Explain why or why not. How can the presence of water affect the conformation of a protein? | + | * Discuss the form of the free energy profile and comment on what is the most stable state of the protein. |
- | + | | |
- | <note tip> | + | *__Tip 2__: In order to understand whether the result obtained from thermodynamic integration is physical or not, have a look at the '' |
- | * We have provided you with a useful script called " | + | * The two articles at the links below show how the free energy profile should look like, using thermodynamic integration or a different enhanced sampling method. Compare the free energy profile obtained from your simulations to either |
+ | * __Paper 1__: [[ https:// | ||
+ | * __Paper 2__: [[ https:// | ||
+ | * Finally, in principle we could have performed a direct MD simulation (as we did in the past exercises) to compute the free energy profile as a function | ||
- | * From the file containing the average force as a function of collective variable you need to integrate $F(x) dx$ numerically to obtain $\Delta A$. You may use the trapezoidal rule (or equivalent) with EXCEL, ORIGIN or any scripting language. | + | <note tip> |
+ | * We have provided you with a useful script called '' | ||
+ | * In order to check the convergence of the free energy profile one should look at the error on the average force for each constrained MD simulation. The error on the free energy profile can be obtained by propagating the error on the average force upon integration. | ||
+ | | ||
</ | </ | ||
<note warning> | <note warning> | ||
- | Make sure that you get the units right when performing the integration. The Largange multipliers are written in atomic units (Hartree/ | + | Make sure that you get the units right when performing the integration. The Largange multipliers are written in atomic units (Hartree/ |
</ | </ | ||
exercises/2018_uzh_acpc2/prot_fol.txt · Last modified: 2020/08/21 10:15 by 127.0.0.1