From a6e061958fd0c598361a27eba25443edc00ce109 Mon Sep 17 00:00:00 2001
From: Zhefu Li <zf-li23@mails.tsinghua.edu.cn>
Date: Tue, 1 Oct 2024 11:22:02 +0000
Subject: [PATCH] Update model.html
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</ul>
</li>
</ul>
+ <h3>2. Force field parameterization</h3>
+ <h4>1. Select Force Field:</h4>
+ <ul>
+ <li>To perform molecular dynamics simulations, it is necessary to choose an appropriate molecular
+ force field to describe the interactions between molecules within the system. CHARMM36 was
+ selected as the force field for protein and small molecule (musk ketone) interactions. However,
+ due to the absence of direct parameters for musk ketone in existing force fields, custom
+ parameters need to be generated to supplement it.</li>
+ </ul>
+ <h4>2. Generate Force Field Parameters:</h4>
+ <ul>
+ <li>Use Avogadro to convert to <code>.mol2</code> format, adjust file information, and then use the
+ software <a href="https://cgenff.com/">CGenFF</a> to generate its CHARMM36 force field parameter
+ file <code>MUS_fix.mol2</code> and parameter file <code>MUS.str</code>. This step includes
+ calculating the sorting of the chemical information file (<code>sort_mol2_bonds.pl</code>) to
+ ensure file correctness.</li>
+ </ul>
+ <pre><code>perl sort_mol2_bonds.pl MUS.mol2 MUS_fix.mol2</code></pre>
+ <h3>3. Preprocessing</h3>
+ <h4>1. Build the system:</h4>
+ <ul>
+ <li>Generate the topology file <code>MOR_processed.gro</code> for the receptor using GROMACS's
+ <code>pdb2gmx</code> command.
+ </li>
+ <pre><code>gmx pdb2gmx -f MOR.pdb -o MOR_processed.gro -ter</code></pre>
+
+ <li>Convert the force field parameters of muscone to a format recognizable by GROMACS to generate
+ its topology data using the CGenFF helper script.</li>
+ <pre><code>python cgenff_charmm2gmx_py3_nx2.py MUS MUS_fix.mol2 MUS.str charmm36-jul2022.ff</code></pre>
+ </ul>
+
+ <h4>2. Merge the system:</h4>
+ <ul>
+ <li>Prepare the complete solvent system required for simulations using the <code>editconf</code> and
+ <code>solvate</code> commands, merging the topology files of muscone <code>mus.gro</code> and
+ receptor <code>MOR_processed.gro</code> into a single system <code>complex.gro</code>.
+ </li>
+ <pre><code>gmx editconf -f mus_ini.pdb -o mus.gro
+ gmx editconf -f complex.gro -o newbox.gro -bt dodecahedron -d 1.0</code></pre>
+
+ <li>Solvate the system in solvent (such as water). From <code>topol.top</code>, it is known that the
+ net charge is 9; add counterions to neutralize the system.</li>
+ <pre><code>gmx editconf -f complex.gro -o newbox.gro -bt dodecahedron -d 1.0
+ gmx solvate -cp newbox.gro -cs spc216.gro -p topol.top -o solv.gro
+ gmx grompp -f ions.mdp -c solv.gro -p topol.top -o ions.tpr
+ gmx genion -s ions.tpr -o solv_ions.gro -p topol.top -pname NA -nname CL -neutral</code></pre>
+ <pre><code>[ molecules ]
+ ; Compound #mols
+ Protein_chain_A 1
+ MUS 1
+ SOL 31227
+ CL 9</code></pre>
+ </ul>
+
+ <h4>3. Energy minimization:</h4>
+ <ul>
+ <li>Perform energy minimization on the overall system to eliminate unreasonable conflicts in the
+ initial geometry. Achieve rapid convergence of energy through the gradient descent algorithm and
+ ensure all atoms in the system are reasonably positioned within the force field. Analyze the
+ energy minimization results to ensure both the maximum force and potential energy are within
+ reasonable thresholds.</li>
+ <pre><code>gmx grompp -f em.mdp -c solv_ions.gro -p topol.top -o em.tpr
+ gmx mdrun -v -deffnm em
+
+ Steepest Descents converged to Fmax < 1000 in 1182 steps
+ Potential Energy = -1.5345670e+06
+ Maximum force = 8.9675085e+02 on atom 4987
+ Norm of force = 1.3456365e+01</code></pre>
+
+ <pre><code>gmx energy -f em.edr -o potential.xvg
+ #11 0
+ xmgrace potential.xvg
+ dit xvg_show -f potential.xvg</code></pre>
+ <div class="image-container">
+ <img src="https://static.igem.wiki/teams/5187/wiki-model-fig/potential.png" alt="potential"
+ class="shadowed-image" style="width: 50%; max-width: 500px;">
+ </div>
+ <p style="text-align: center; font-size: 0.9em; margin-top: 10px;">fig 8 Potential Energy
+ Minimization</p>
+ </ul>
+ <h3>4. Molecular Dynamics Simulation</h3>
+ <h4>1. System Equilibration:</h4>
+ <ul>
+ <li>To achieve thermal and mechanical equilibrium of the system, simulations are conducted in two
+ stages: NVT (constant temperature) and NPT (constant pressure) equilibration. The system
+ temperature is gradually increased to the target of 300K to reach stable conditions, while
+ analyzing the curves of temperature, pressure, and density over time to ensure the stability of
+ the system.</li>
+ </ul>
+
+ <pre><code>gmx grompp -f nvt.mdp -c em.gro -r em.gro -p topol.top -n index.ndx -o nvt.tpr
+ gmx mdrun -deffnm nvt
+ gmx energy -f nvt.edr -o temperature.xvg
+ #16 0
+ dit xvg_show -f temperature.xvg
+ </code></pre>
+ <img src="2.temperature.png" alt="">
+ <img src="temperature.png" alt="">
+
+ <pre><code>gmx grompp -f npt.mdp -c nvt.gro -t nvt.cpt -r nvt.gro -p topol.top -n index.ndx -o npt.tpr -maxwarn 1
+ gmx mdrun -deffnm npt
+ gmx energy -f npt.edr -o pressure.xvg
+ #17 0
+ gmx energy -f npt.edr -o density.xvg
+ #23 0
+ dit xvg_show -f temperature.xvg
+ </code></pre>
+ <div class="image-container">
+ <img src="https://static.igem.wiki/teams/5187/wiki-model-fig/3-pressure.png" alt="pressure"
+ class="shadowed-image" style="width: 50%; max-width: 500px;">
+ </div>
+ <p style="text-align: center; font-size: 0.9em; margin-top: 10px;">fig 9 Curve of the pressure over time
+ </p>
+ <div class="image-container">
+ <img src="https://static.igem.wiki/teams/5187/wiki-model-fig/density.png" alt="density"
+ class="shadowed-image" style="width: 50%; max-width: 500px;">
+ </div>
+ <p style="text-align: center; font-size: 0.9em; margin-top: 10px;">fig 10 Curve of the density over time
+ </p>
+ <h4>2. Production Simulation:</h4>
+ <ul>
+ <li>Under the conditions of equilibrium, a long-term production simulation is conducted. This
+ simulation observes the time evolution characteristics of the dynamic interactions between
+ muscone and the receptor, typically requiring simulation times ranging from hundreds of
+ nanoseconds to several microseconds to ensure the reliability and reproducibility of the
+ results. By sampling key frame data of the system during the dynamic process, it aids in further
+ analyzing the intermolecular interactions and dynamic conformational changes.</li>
+ </ul>
+
+ <pre><code>gmx grompp -f md.mdp -c npt.gro -t npt.cpt -p topol.top -n index.ndx -o md_0_10.tpr
+ gmx mdrun -deffnm md_0_10
+ </code></pre>
+ <div class="image-container">
+ <img src="https://static.igem.wiki/teams/5187/wiki-model-fig/mds.png" alt="MDS"
+ class="shadowed-image" style="width: 50%; max-width: 500px;">
+ </div>
+ <p style="text-align: center; font-size: 0.9em; margin-top: 10px;">fig 11 Molecular dynamics simulation
+ process
+ </p>
+ <div class="image-container">
+ <img src="https://static.igem.wiki/teams/5187/wiki-model-fig/density.png" alt="density"
+ class="shadowed-image" style="width: 50%; max-width: 500px;">
+ </div>
+ <p style="text-align: center; font-size: 0.9em; margin-top: 10px;">fig 12 Results of the molecular
+ dynamics simulations
+ </p>
</div>
</div>
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