Re: [gmx-users] [gmx-user] Autodock Vina Out use in gromacs MD
On 1/4/20 1:17 PM, Quin K wrote: Dear Proffesor Lemkul, I have given below the MD RMSD for complex, and noted that Ligand is getting detached again. When I viewed the trajectory on VMD it was confirmed. The ligand did not abruptly got dislodged instead it slowly came out of binding pocket and started moving around after. https://drive.google.com/file/d/1IBMU-8SzSgXVr_h9zyeVwNV7kQ4at8-S/view?usp=sharing It would be more useful to investigate which interactions are broken first or if there is a dihedral that rotates that leads to a conformational change in the ligand. RMSD tells you very little. I know that following CGenFF tutorial and fixing the molecule and reparameterization would be the correct thing to do however I lack time at this moment. I read the paper and went through the tutorial and it's some what of a complex method to fix the parameters. I was thinking if I should use a different force-field such as Gromos with parameterization with ATB server. I have already submitted the given molecule below for optimization in ATB and the parameterization is now complete. Other option is to use Amber force field. Kindly let me know what your opinion on this. The nice thing about CGenFF is it tells you where it thinks problems might be and how they score in terms of quality. Neither of the other options do that. You always need to validate a ligand topology. Black boxes might work well or they might work poorly. You just don't know. Molecule https://drive.google.com/file/d/1Ni8rUX4sH3aKaRhhXqCZr9w8VJVetCI7/view?usp=sharing Interactions at binding site us DS Visualizer https://drive.google.com/file/d/16EkWYDPDyTfkERiQgaOYo4XxYxqslOD0/view?usp=sharing Also please let me know if you think the given interactions are enough to keep the molecule at binding site for like 100ns? The Arg-ligand interaction should be pretty strong, but you have an identified "unfavorable" contact (which could be due to the rotameric state of Asn111 being suboptimal, and otherwise only nonpolar contacts. I wouldn't expect a very favorable binding free energy. -Justin -- == Justin A. Lemkul, Ph.D. Assistant Professor Office: 301 Fralin Hall Lab: 303 Engel Hall Virginia Tech Department of Biochemistry 340 West Campus Dr. Blacksburg, VA 24061 jalem...@vt.edu | (540) 231-3129 http://www.thelemkullab.com == -- Gromacs Users mailing list * Please search the archive at http://www.gromacs.org/Support/Mailing_Lists/GMX-Users_List before posting! * Can't post? Read http://www.gromacs.org/Support/Mailing_Lists * For (un)subscribe requests visit https://maillist.sys.kth.se/mailman/listinfo/gromacs.org_gmx-users or send a mail to gmx-users-requ...@gromacs.org.
Re: [gmx-users] [gmx-user] Autodock Vina Out use in gromacs MD
Dear Proffesor Lemkul, I have given below the MD RMSD for complex, and noted that Ligand is getting detached again. When I viewed the trajectory on VMD it was confirmed. The ligand did not abruptly got dislodged instead it slowly came out of binding pocket and started moving around after. https://drive.google.com/file/d/1IBMU-8SzSgXVr_h9zyeVwNV7kQ4at8-S/view?usp=sharing I know that following CGenFF tutorial and fixing the molecule and reparameterization would be the correct thing to do however I lack time at this moment. I read the paper and went through the tutorial and it's some what of a complex method to fix the parameters. I was thinking if I should use a different force-field such as Gromos with parameterization with ATB server. I have already submitted the given molecule below for optimization in ATB and the parameterization is now complete. Other option is to use Amber force field. Kindly let me know what your opinion on this. Molecule https://drive.google.com/file/d/1Ni8rUX4sH3aKaRhhXqCZr9w8VJVetCI7/view?usp=sharing Interactions at binding site us DS Visualizer https://drive.google.com/file/d/16EkWYDPDyTfkERiQgaOYo4XxYxqslOD0/view?usp=sharing Also please let me know if you think the given interactions are enough to keep the molecule at binding site for like 100ns? Thank you in Advance! Kind Regards Q On Tue, Dec 31, 2019 at 9:21 AM Justin Lemkul wrote: > > > On 12/30/19 1:51 PM, Quin K wrote: > > Further to following email, is it OK to do an energy minimization with > > Gaussian16 so the molecule is refined before MD simulation with Gromacs? > > What would be the purpose? A gas-phase optimized geometry has no > relationship to the pose adopted by a molecule upon binding to its > receptor. > > > If such an energy minimization is done should I use DFT ? > > Depends on the force field you're using. Most biomolecular force fields > do not use DFT for most calculations. If this goes back to our original > discussion about your CGenFF parameters, I beg you to follow the advice > I already gave - read the CGenFF paper. It tells you the *exact* model > chemistries you should use for everything to ensure compatibility with > the CHARMM force field. > > > Would that affect the orientation at which molecule was docked with > > protein? > > No, because the docking software changes the configuration. > > -Justin > > > > > On Mon, Dec 30, 2019 at 8:35 PM Quin K wrote: > > > >> Hi > >> > >> I noted when I used Autodock vina for docking and used the converted > back > >> .mol2 file from .pdbqt format, there were a lot of changes in the > molecule > >> than the molecule I initially submitted to Vina for docking. Like the > *atomic > >> charges were different. * > >> Is this normal? or is there a way to use the original DFT optimized > >> molecule with current docking orientation of Vina output file?? > >> Also noted that there were missing atoms like hydrogens. > >> Last time I tried this simulation the ligand got detached from binding > >> site after like 20 ns. This could probably be a main reason for that > >> because I never refined the molecule to adjust for changed charges etc. > >> > >> Kindly give your opinion > >> Thanks! > >> Regards! > >> > > -- > == > > Justin A. Lemkul, Ph.D. > Assistant Professor > Office: 301 Fralin Hall > Lab: 303 Engel Hall > > Virginia Tech Department of Biochemistry > 340 West Campus Dr. > Blacksburg, VA 24061 > > jalem...@vt.edu | (540) 231-3129 > http://www.thelemkullab.com > > == > > -- > Gromacs Users mailing list > > * Please search the archive at > http://www.gromacs.org/Support/Mailing_Lists/GMX-Users_List before > posting! > > * Can't post? Read http://www.gromacs.org/Support/Mailing_Lists > > * For (un)subscribe requests visit > https://maillist.sys.kth.se/mailman/listinfo/gromacs.org_gmx-users or > send a mail to gmx-users-requ...@gromacs.org. > -- Gromacs Users mailing list * Please search the archive at http://www.gromacs.org/Support/Mailing_Lists/GMX-Users_List before posting! * Can't post? Read http://www.gromacs.org/Support/Mailing_Lists * For (un)subscribe requests visit https://maillist.sys.kth.se/mailman/listinfo/gromacs.org_gmx-users or send a mail to gmx-users-requ...@gromacs.org.
Re: [gmx-users] [gmx-user] Autodock Vina Out use in gromacs MD
On 12/30/19 1:51 PM, Quin K wrote: Further to following email, is it OK to do an energy minimization with Gaussian16 so the molecule is refined before MD simulation with Gromacs? What would be the purpose? A gas-phase optimized geometry has no relationship to the pose adopted by a molecule upon binding to its receptor. If such an energy minimization is done should I use DFT ? Depends on the force field you're using. Most biomolecular force fields do not use DFT for most calculations. If this goes back to our original discussion about your CGenFF parameters, I beg you to follow the advice I already gave - read the CGenFF paper. It tells you the *exact* model chemistries you should use for everything to ensure compatibility with the CHARMM force field. Would that affect the orientation at which molecule was docked with protein? No, because the docking software changes the configuration. -Justin On Mon, Dec 30, 2019 at 8:35 PM Quin K wrote: Hi I noted when I used Autodock vina for docking and used the converted back .mol2 file from .pdbqt format, there were a lot of changes in the molecule than the molecule I initially submitted to Vina for docking. Like the *atomic charges were different. * Is this normal? or is there a way to use the original DFT optimized molecule with current docking orientation of Vina output file?? Also noted that there were missing atoms like hydrogens. Last time I tried this simulation the ligand got detached from binding site after like 20 ns. This could probably be a main reason for that because I never refined the molecule to adjust for changed charges etc. Kindly give your opinion Thanks! Regards! -- == Justin A. Lemkul, Ph.D. Assistant Professor Office: 301 Fralin Hall Lab: 303 Engel Hall Virginia Tech Department of Biochemistry 340 West Campus Dr. Blacksburg, VA 24061 jalem...@vt.edu | (540) 231-3129 http://www.thelemkullab.com == -- Gromacs Users mailing list * Please search the archive at http://www.gromacs.org/Support/Mailing_Lists/GMX-Users_List before posting! * Can't post? Read http://www.gromacs.org/Support/Mailing_Lists * For (un)subscribe requests visit https://maillist.sys.kth.se/mailman/listinfo/gromacs.org_gmx-users or send a mail to gmx-users-requ...@gromacs.org.
Re: [gmx-users] [gmx-user] Autodock Vina Out use in gromacs MD
On 12/30/19 10:05 AM, Quin K wrote: Hi I noted when I used Autodock vina for docking and used the converted back .mol2 file from .pdbqt format, there were a lot of changes in the molecule than the molecule I initially submitted to Vina for docking. Like the *atomic charges were different. * Is this normal? or is there a way to use the original DFT optimized molecule with current docking orientation of Vina output file?? Consult the Vina documentation for how to control topology aspects like charges. Also noted that there were missing atoms like hydrogens. This is also probably a Vina convention, to speed up the calculation. This would explain why charges changed. You can't just delete hydrogens without accounting for their partial charges. Last time I tried this simulation the ligand got detached from binding site after like 20 ns. This could probably be a main reason for that because I never refined the molecule to adjust for changed charges etc. The topology you used for MD and the charges used in docking likely have no relationship to one another, and if the pose was really that heavily influenced by these factors, you probably would have observed a change in the binding pose even after energy minimization. -Justin -- == Justin A. Lemkul, Ph.D. Assistant Professor Office: 301 Fralin Hall Lab: 303 Engel Hall Virginia Tech Department of Biochemistry 340 West Campus Dr. Blacksburg, VA 24061 jalem...@vt.edu | (540) 231-3129 http://www.thelemkullab.com == -- Gromacs Users mailing list * Please search the archive at http://www.gromacs.org/Support/Mailing_Lists/GMX-Users_List before posting! * Can't post? Read http://www.gromacs.org/Support/Mailing_Lists * For (un)subscribe requests visit https://maillist.sys.kth.se/mailman/listinfo/gromacs.org_gmx-users or send a mail to gmx-users-requ...@gromacs.org.
Re: [gmx-users] [gmx-user] Autodock Vina Out use in gromacs MD
Further to following email, is it OK to do an energy minimization with Gaussian16 so the molecule is refined before MD simulation with Gromacs? If such an energy minimization is done should I use DFT ? Would that affect the orientation at which molecule was docked with protein? On Mon, Dec 30, 2019 at 8:35 PM Quin K wrote: > Hi > > I noted when I used Autodock vina for docking and used the converted back > .mol2 file from .pdbqt format, there were a lot of changes in the molecule > than the molecule I initially submitted to Vina for docking. Like the *atomic > charges were different. * > Is this normal? or is there a way to use the original DFT optimized > molecule with current docking orientation of Vina output file?? > Also noted that there were missing atoms like hydrogens. > Last time I tried this simulation the ligand got detached from binding > site after like 20 ns. This could probably be a main reason for that > because I never refined the molecule to adjust for changed charges etc. > > Kindly give your opinion > Thanks! > Regards! > -- Gromacs Users mailing list * Please search the archive at http://www.gromacs.org/Support/Mailing_Lists/GMX-Users_List before posting! * Can't post? Read http://www.gromacs.org/Support/Mailing_Lists * For (un)subscribe requests visit https://maillist.sys.kth.se/mailman/listinfo/gromacs.org_gmx-users or send a mail to gmx-users-requ...@gromacs.org.
[gmx-users] [gmx-user] Autodock Vina Out use in gromacs MD
Hi I noted when I used Autodock vina for docking and used the converted back .mol2 file from .pdbqt format, there were a lot of changes in the molecule than the molecule I initially submitted to Vina for docking. Like the *atomic charges were different. * Is this normal? or is there a way to use the original DFT optimized molecule with current docking orientation of Vina output file?? Also noted that there were missing atoms like hydrogens. Last time I tried this simulation the ligand got detached from binding site after like 20 ns. This could probably be a main reason for that because I never refined the molecule to adjust for changed charges etc. Kindly give your opinion Thanks! Regards! -- Gromacs Users mailing list * Please search the archive at http://www.gromacs.org/Support/Mailing_Lists/GMX-Users_List before posting! * Can't post? Read http://www.gromacs.org/Support/Mailing_Lists * For (un)subscribe requests visit https://maillist.sys.kth.se/mailman/listinfo/gromacs.org_gmx-users or send a mail to gmx-users-requ...@gromacs.org.
