molecular dynamics with phosphates: monobasic form unstable?
I am having my students model dipeptides where one residue is a phosphorylated serine or threonine. Molecular dynamics with the dibasic phosphate works fine. However, the student NMR data for their dipeptides is acquired at low pH, so I would like them to be able to model the monobasic form. Unfortunately, all my attempts at creating a monobasic form have resulted in the molecule "blowing up" in MD, first by crazily shaking the phosphate as if it wants to dislodge the proton, and then the entire molecule until it fragments. I have tried building these from scratch by various methods (e.g. those listed in http://plato.cgl.ucsf.edu/pipermail/chimera-users/2012-January/007068.html ) as well as using SwissSidechain and mutating residues. I have tried exporting as a .pdb, opening in PyMOL to make sure everything looks OK, resaving as .pdb and importing PyMOL's version. I have also used a protein from PDB that had a TPO residue assigned, and snipped it down to a dipeptide.For both this manner of construction, and for building the dipeptide from scratch with SwissSidechain, Chimera interprets SwissSidechain's TPO (pThr monobasic) and SEP (pSer monobasic) as their dibasic forms (TPO2 and SEP2 respectively). PyMOL interprets these structures with the correct level of protonation, however. Is there a known issue with Chimera and treatment of [-OPO3H]-1 groups, or have I managed to make the same error across multiple build methods? -- Dr. Geoffrey Sametz QDH 104 Department of Chemistry and Biochemistry University of Delaware sametz@udel.edu (302) 831-3621
Hi Geoffrey, I don’t think anybody has tried the Chimera dynamics tool with phosphorylated sidechains. The minimization/MD tools in Chimera are fairly limited and slow (no cutoffs or sophisticated handling of long-range electrostatics, no detailed control over residue parameters) compared to dedicated programs like GROMACS and AMBER, so most detailed research with MD, as opposed to brief explorations of flexibility or structure cleanup, would use one of those dedicated packages instead. I can answer the part about protonation and adding charges in Chimera, but whether it will attain stability in simulation may be a separate matter. Before you add hydrogens, just change the automatically assigned atom type of the oxygen you wish to protonate to O3. I can see for example with the TPO in 1guf chain A that the three terminal oxygens are automatically given type O3- open 6guf delete ~protein delete ~:.a disp :tpo focus :tpo labelopt info idatmType label :tpo (… select the oxygen you want to change with Ctrl-click) setattr a idatmType O3 sel label sel addh addcharge (...TPO is now estimated as charge -1, OK) I tried 100 steps steepest descent minimization, selecting a zone within 4A of TPO and allowing only those atoms to move, and it didn’t move much. I hope this helps, Elaine ----- Elaine C. Meng, Ph.D. UCSF Chimera(X) team Department of Pharmaceutical Chemistry University of California, San Francisco
On Mar 30, 2019, at 11:31 AM, Geoffrey Sametz <sametz@udel.edu> wrote:
I am having my students model dipeptides where one residue is a phosphorylated serine or threonine. Molecular dynamics with the dibasic phosphate works fine. However, the student NMR data for their dipeptides is acquired at low pH, so I would like them to be able to model the monobasic form. Unfortunately, all my attempts at creating a monobasic form have resulted in the molecule "blowing up" in MD, first by crazily shaking the phosphate as if it wants to dislodge the proton, and then the entire molecule until it fragments.
I have tried building these from scratch by various methods (e.g. those listed in http://plato.cgl.ucsf.edu/pipermail/chimera-users/2012-January/007068.html ) as well as using SwissSidechain and mutating residues. I have tried exporting as a .pdb, opening in PyMOL to make sure everything looks OK, resaving as .pdb and importing PyMOL's version.
I have also used a protein from PDB that had a TPO residue assigned, and snipped it down to a dipeptide.For both this manner of construction, and for building the dipeptide from scratch with SwissSidechain, Chimera interprets SwissSidechain's TPO (pThr monobasic) and SEP (pSer monobasic) as their dibasic forms (TPO2 and SEP2 respectively). PyMOL interprets these structures with the correct level of protonation, however.
Is there a known issue with Chimera and treatment of [-OPO3H]-1 groups, or have I managed to make the same error across multiple build methods?
-- Dr. Geoffrey Sametz QDH 104 Department of Chemistry and Biochemistry University of Delaware sametz@udel.edu (302) 831-3621 _______________________________________________ Chimera-users mailing list: Chimera-users@cgl.ucsf.edu Manage subscription: http://plato.cgl.ucsf.edu/mailman/listinfo/chimera-users
Thanks for your help! Unfortunately, in my hands, this as well produces a phosphate that blows up, both for your exact example and also as applied to my cases. I tried uninstalling SwissSidechain as well, but to no effect. Generally, the phosphate becomes agitated with severe conformations and steric clashes (e.g. you see things like one O bonding to another O to form a three-membered OPO ring, but with a hydrogen superimposed on an O). The agitation increases across the molecule until it "explodes" into pieces. I'm going to work with the well-behaved dibasic phosphate for now.... I'm just recording my experience here in the email record in case it helps someone else. On Sat, Mar 30, 2019 at 4:44 PM Elaine Meng <meng@cgl.ucsf.edu> wrote:
Hi Geoffrey, I don’t think anybody has tried the Chimera dynamics tool with phosphorylated sidechains. The minimization/MD tools in Chimera are fairly limited and slow (no cutoffs or sophisticated handling of long-range electrostatics, no detailed control over residue parameters) compared to dedicated programs like GROMACS and AMBER, so most detailed research with MD, as opposed to brief explorations of flexibility or structure cleanup, would use one of those dedicated packages instead.
I can answer the part about protonation and adding charges in Chimera, but whether it will attain stability in simulation may be a separate matter.
Before you add hydrogens, just change the automatically assigned atom type of the oxygen you wish to protonate to O3. I can see for example with the TPO in 1guf chain A that the three terminal oxygens are automatically given type O3-
open 6guf delete ~protein delete ~:.a disp :tpo focus :tpo labelopt info idatmType label :tpo
(… select the oxygen you want to change with Ctrl-click)
setattr a idatmType O3 sel label sel
addh addcharge (...TPO is now estimated as charge -1, OK)
I tried 100 steps steepest descent minimization, selecting a zone within 4A of TPO and allowing only those atoms to move, and it didn’t move much.
I hope this helps, Elaine ----- Elaine C. Meng, Ph.D. UCSF Chimera(X) team Department of Pharmaceutical Chemistry University of California, San Francisco
On Mar 30, 2019, at 11:31 AM, Geoffrey Sametz <sametz@udel.edu> wrote:
I am having my students model dipeptides where one residue is a phosphorylated serine or threonine. Molecular dynamics with the dibasic phosphate works fine. However, the student NMR data for their dipeptides is acquired at low pH, so I would like them to be able to model the monobasic form. Unfortunately, all my attempts at creating a monobasic form have resulted in the molecule "blowing up" in MD, first by crazily shaking the phosphate as if it wants to dislodge the proton, and then the entire molecule until it fragments.
I have tried building these from scratch by various methods (e.g. those listed in http://plato.cgl.ucsf.edu/pipermail/chimera-users/2012-January/007068.html ) as well as using SwissSidechain and mutating residues. I have tried exporting as a .pdb, opening in PyMOL to make sure everything looks OK, resaving as .pdb and importing PyMOL's version.
I have also used a protein from PDB that had a TPO residue assigned, and snipped it down to a dipeptide.For both this manner of construction, and for building the dipeptide from scratch with SwissSidechain, Chimera interprets SwissSidechain's TPO (pThr monobasic) and SEP (pSer monobasic) as their dibasic forms (TPO2 and SEP2 respectively). PyMOL interprets these structures with the correct level of protonation, however.
Is there a known issue with Chimera and treatment of [-OPO3H]-1 groups, or have I managed to make the same error across multiple build methods?
-- Dr. Geoffrey Sametz QDH 104 Department of Chemistry and Biochemistry University of Delaware sametz@udel.edu (302) 831-3621 _______________________________________________ Chimera-users mailing list: Chimera-users@cgl.ucsf.edu Manage subscription: http://plato.cgl.ucsf.edu/mailman/listinfo/chimera-users
-- Dr. Geoffrey Sametz QDH 104 Department of Chemistry and Biochemistry University of Delaware sametz@udel.edu (302) 831-3621
Antechamber assigns GAFF atom types to the atoms of the non-standard TPO residue which, as per the first two letters of GAFF, are generic Amber atom types. The forcefield files shipped with AmberTools do not have parameters for the bond lengths, angles, and dihedral angles formed by the protonated GAFF-typed phosphate and therefore that proton does non-physical things during the simulation and the simulation blows up. You would pretty much have to work with AmberTools directly and do some parameterization work in order to simulate this system — it’s kind of beyond what Chimera is directly capable of. —Eric Eric Pettersen UCSF Computer Graphics Lab
On Apr 1, 2019, at 12:14 PM, Geoffrey Sametz <sametz@udel.edu> wrote:
Thanks for your help! Unfortunately, in my hands, this as well produces a phosphate that blows up, both for your exact example and also as applied to my cases. I tried uninstalling SwissSidechain as well, but to no effect.
Generally, the phosphate becomes agitated with severe conformations and steric clashes (e.g. you see things like one O bonding to another O to form a three-membered OPO ring, but with a hydrogen superimposed on an O). The agitation increases across the molecule until it "explodes" into pieces.
I'm going to work with the well-behaved dibasic phosphate for now.... I'm just recording my experience here in the email record in case it helps someone else.
On Sat, Mar 30, 2019 at 4:44 PM Elaine Meng <meng@cgl.ucsf.edu <mailto:meng@cgl.ucsf.edu>> wrote: Hi Geoffrey, I don’t think anybody has tried the Chimera dynamics tool with phosphorylated sidechains. The minimization/MD tools in Chimera are fairly limited and slow (no cutoffs or sophisticated handling of long-range electrostatics, no detailed control over residue parameters) compared to dedicated programs like GROMACS and AMBER, so most detailed research with MD, as opposed to brief explorations of flexibility or structure cleanup, would use one of those dedicated packages instead.
I can answer the part about protonation and adding charges in Chimera, but whether it will attain stability in simulation may be a separate matter.
Before you add hydrogens, just change the automatically assigned atom type of the oxygen you wish to protonate to O3. I can see for example with the TPO in 1guf chain A that the three terminal oxygens are automatically given type O3-
open 6guf delete ~protein delete ~:.a disp :tpo focus :tpo labelopt info idatmType label :tpo
(… select the oxygen you want to change with Ctrl-click)
setattr a idatmType O3 sel label sel
addh addcharge (...TPO is now estimated as charge -1, OK)
I tried 100 steps steepest descent minimization, selecting a zone within 4A of TPO and allowing only those atoms to move, and it didn’t move much.
I hope this helps, Elaine ----- Elaine C. Meng, Ph.D. UCSF Chimera(X) team Department of Pharmaceutical Chemistry University of California, San Francisco
On Mar 30, 2019, at 11:31 AM, Geoffrey Sametz <sametz@udel.edu <mailto:sametz@udel.edu>> wrote:
I am having my students model dipeptides where one residue is a phosphorylated serine or threonine. Molecular dynamics with the dibasic phosphate works fine. However, the student NMR data for their dipeptides is acquired at low pH, so I would like them to be able to model the monobasic form. Unfortunately, all my attempts at creating a monobasic form have resulted in the molecule "blowing up" in MD, first by crazily shaking the phosphate as if it wants to dislodge the proton, and then the entire molecule until it fragments.
I have tried building these from scratch by various methods (e.g. those listed in http://plato.cgl.ucsf.edu/pipermail/chimera-users/2012-January/007068.html <http://plato.cgl.ucsf.edu/pipermail/chimera-users/2012-January/007068.html> ) as well as using SwissSidechain and mutating residues. I have tried exporting as a .pdb, opening in PyMOL to make sure everything looks OK, resaving as .pdb and importing PyMOL's version.
I have also used a protein from PDB that had a TPO residue assigned, and snipped it down to a dipeptide.For both this manner of construction, and for building the dipeptide from scratch with SwissSidechain, Chimera interprets SwissSidechain's TPO (pThr monobasic) and SEP (pSer monobasic) as their dibasic forms (TPO2 and SEP2 respectively). PyMOL interprets these structures with the correct level of protonation, however.
Is there a known issue with Chimera and treatment of [-OPO3H]-1 groups, or have I managed to make the same error across multiple build methods?
-- Dr. Geoffrey Sametz QDH 104 Department of Chemistry and Biochemistry University of Delaware sametz@udel.edu <mailto:sametz@udel.edu> (302) 831-3621 _______________________________________________ Chimera-users mailing list: Chimera-users@cgl.ucsf.edu <mailto:Chimera-users@cgl.ucsf.edu> Manage subscription: http://plato.cgl.ucsf.edu/mailman/listinfo/chimera-users <http://plato.cgl.ucsf.edu/mailman/listinfo/chimera-users>
-- Dr. Geoffrey Sametz QDH 104 Department of Chemistry and Biochemistry University of Delaware sametz@udel.edu <mailto:sametz@udel.edu> (302) 831-3621 _______________________________________________ Chimera-users mailing list: Chimera-users@cgl.ucsf.edu Manage subscription: http://plato.cgl.ucsf.edu/mailman/listinfo/chimera-users
participants (3)
-
Elaine Meng -
Eric Pettersen -
Geoffrey Sametz