Re: AW: stereo-chemical inversion during MD

From: Branko (bdrakuli_at_chem.bg.ac.rs)
Date: Tue May 08 2012 - 15:03:08 CDT

Gordon,

I have no idea and never seen such mobility, especially of the -NH3
after the inversion. Axel most probably can offer some useful advice. In
2A5T there is 3 water molecules that makes bridged H bonds: NH3 (HOH
2019) and terminal COOH (HOH 2017 and 2004). Maybe you can try to
include this water molecules (I could suggests GRID and -6 kcal/mol as
reasonable for exact positioning, see J. Chem. Inf. Model. 2011, 51,
2860--2867). Also try to check pronation state of your ligand by Propka
(http://propka.ki.ku.dk/), vicinal residues can dramatically changes
pKa, and propka uses empirical function for estimation. If you prepare
protein-ligand complex for Desmond by Maestro, and use protein
preparation wizard, one step include optimization of the H-bonds
network, so this also can make difference.

Branko

On 5/8/2012 9:04 PM, Gordon Wells wrote:
> Hi
>
> Thanks for the helpful replies.
>
> It is indeed a case of overcoming a high energy barrier and it seems
> to be primed by the starting conformation, first minimisation
> squashing the bond angle (I accidentally included both conformations
> in the second attachment above), and then large initial forces during
> relaxation (after reading the paper Francesco cited). I've attached an
> .mpg of the first few frames during equilibration in the
> protein-ligand complex (I tried starting the relaxation at 10K and
> 60K). While based on a homology model, the l-glu (ligand) conformation
> is exactly as in the template (2A5T). This protein family also binds
> d-glu and I've observed inversion for that ligand too.
>
> It seems adding restraints during the relaxation stage with the
> chirality plugin is needed here. But I'm still curious as to what the
> other MD packages I tried are doing differently?
>
> Regards
> Gordon
>
>
> -- max(?(??????????)dt)
>
> Dr Gordon Wells
> Chemistry Department
> Emory University
> Atlanta, Georgia, USA
>
>
>
> On 8 May 2012 11:51, Branko <bdrakuli_at_chem.bg.ac.rs
> <mailto:bdrakuli_at_chem.bg.ac.rs>> wrote:
>
> Axel,
>
> This is valuable information, still I didn't faced with similar
> situation so far. Also, I can suppose than something like this is
> possible for sp3 N, still cannot imagine such high energy
> intermediate of sp3 C. On the other hand Gordon simulate one amino
> acid in explicit solvent and obtain stereochemical inversion. Did
> he start with conformer of unrealistic high energy. In protein,
> surroundings can constrain this residue in such conformation,
> still think that something in initial settings did not work
> perfectly. Maybe high temperature or similar, also there is no
> information about origin of the starting protein, taken from the
> PDB, modeled. Gordon state that can overcome problem by
> 'increasing the di-electric or decreasing the partial charges on
> the ammonium hydrogens'. Is there some metal ions in vicinity.
> Also are free amino acid is comparable with the same one bound in
> the protein; even if this is C terminal amino acid 'NH2' should be
> part of amide bond - so this isn't NH3+...
>
> Branko
>
>
>
>
>
> On 5/8/2012 3:33 PM, Axel Kohlmeyer wrote:
>> On Tue, May 8, 2012 at 4:26 AM, Branko<bdrakuli_at_chem.bg.ac.rs> <mailto:bdrakuli_at_chem.bg.ac.rs> wrote:
>>> Stereochemical inversion implies bond breaking and bond making, and this is
>>> not possible by molecular dynamics and using all atoms force fields. It is
>> i beg to differ. stereochemical inversion is quite possible
>> without bond breaking and particularly with a classical
>> model. all you need is to go through a very high-energy
>> intermediate. and particularly this last condition is what
>> makes it particularly possible for a classical model, since
>> bonds do *not* break in this case. when setting up a
>> simulation and trying to get it to equilibrium, these kind
>> of conditions can happen (and they happen more frequently
>> than people suspect).
>>
>> just consider the case of a asymmetrically substituted
>> methane. all you need is a conformation where all substituents
>> are in the same plane as the central carbon atom. depending
>> on how the planar symmetry is broken, you will get a
>> different stereo isomer.
>>
>> VMD ships with two plugins that help to detect such artefacts:
>>
>> http://www.ks.uiuc.edu/Research/vmd/plugins/chirality/
>> http://www.ks.uiuc.edu/Research/vmd/plugins/cispeptide/
>>
>> cheers,
>> axel.
>>> advisable to carefully check your input PDB file, residue name, atoms etc.
>>>
>>>
>>> On 5/8/2012 8:01 AM, Norman Geist wrote:
>>>
>>> Hi Gordon,
>>>
>>>
>>>
>>> I'm not a specialist for biochemistry, but what you say could make sense as
>>> the minimization looks for the best energy conformation. It could be, that
>>> this angle is a better energy conformation for a particular system. But when
>>> it's bounded to other residues, it would maybe interfere with other side
>>> chains and so would stay with the original angle. That would be easy to try
>>> out. I can hardly imagine that the minimization algorithm can work against
>>> the FF parameters.
>>>
>>>
>>>
>>> Norman Geist.
>>>
>>>
>>>
>>> Von:owner-namd-l_at_ks.uiuc.edu <mailto:owner-namd-l_at_ks.uiuc.edu> [mailto:owner-namd-l_at_ks.uiuc.edu] Im Auftrag
>>> von Gordon Wells
>>> Gesendet: Montag, 7. Mai 2012 19:01
>>> An:namd-l_at_ks.uiuc.edu <mailto:namd-l_at_ks.uiuc.edu>
>>> Betreff: namd-l: stereo-chemical inversion during MD
>>>
>>>
>>>
>>> Hi All
>>>
>>>
>>>
>>> I've encountered a strange situation when simulating a particular
>>> conformation of L-Glu. During minimisation the bond angle between the
>>> carboxyl-C, C-alpha and amino-N decreases from 112 to 89. When this is
>>> subsequently used for MD there is often a stereo-chemical inversion around
>>> the C-alpha. I see this when simulating the system in its original protein
>>> complex and free in solution (TIP3 solvent for both).
>>>
>>>
>>>
>>> I can prevent it by using a very short minimisation (50 instead of 1000
>>> steps), increasing the di-electric or decreasing the partial charges on the
>>> ammonium hydrogens. Nonetheless, I'm sure this strained conformation
>>> shouldn't be produced in the first place (I'm not able to replicate this
>>> behaviour in macromodal or desmond) The force between the carboxyl oxygen
>>> (nearest to the ammonium moiety) and the ammonium hydrogens seems to be too
>>> high.
>>>
>>>
>>>
>>> I've attached before and after pdbs of the free L-glu. I get the distorted
>>> conformation from the following namd input (with and without pbc):
>>>
>>>
>>>
>>> coordinates LGlu_autopsf.pdb
>>>
>>> structure LGlu_autopsf.psf
>>>
>>>
>>>
>>> paratypecharmm on
>>>
>>> parameters par_all27_prot_lipid_na.inp
>>>
>>>
>>>
>>> outputname minall-lglu-only
>>>
>>> binaryoutput yes
>>>
>>> outputenergies 25
>>>
>>>
>>>
>>> switching on
>>>
>>> cutoff 12
>>>
>>> switchdist 10
>>>
>>> pairlistdist 14
>>>
>>> exclude 1-4
>>>
>>>
>>>
>>> fixedAtoms off
>>>
>>>
>>>
>>> numsteps 1000
>>>
>>> dielectric 1
>>>
>>> minimization on
>>>
>>>
>>>
>>> Is this forcefield related, bad input file or possibly a bug in NAMD?
>>>
>>>
>>> -- max(?(??????????)dt)
>>>
>>> Dr Gordon Wells
>>> Chemistry Department
>>>
>>> Emory University
>>>
>>> Atlanta, Georgia, USA
>>>
>>>
>>>
>>>
>>>
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