I want to optimize the DNA ds (CCTGGTCC) structure with an organic drug by using ONIOM (phosphorous in the low level amber force field). As we know that phosphorous is a negatively charged one: should charge modification be needed in the optimization of DNA or not? Also, will freezing of P provide the proper result? Is it necessary?
I assume you plan to optimize the DNA in gas phase... Apart from the questionable meaningfulness of such approach, I guess all what you've suggested people do: neutralize, keep charged or spatially freeze. Each of these have pros and cons. Obviously, the most rigorous is to keep the phosphates charged (since the phosphates in DNA _are_ charge) but then you may face terrible structural deformations of the polyanion in gas phase... Adding hydrogens may yield unrealistic structures too due to artificial hydrogen bonds. What about microhydration? Would you mind to add a few water molecules around the charged phosphates? Another trick could be to use some positional restraints, that means freeze the phosphates 'just a litle'.
Dear Michal,
Your assumption is correct. I am doing the Drug-DNA optimization in the gas phase. Initially i want to do it in the gas phase only. Optimization is going on but structural deformation occurs in this case. So i am in a confusion whether finally (after complete optimization) i will get the proper structure (without deformation) or not. In such case should i use freeze option for all the phosphorous?
The question stands why you optimize in gas phase? Can you imagine DNA in gas phase? If you experimentally manage to isolate DNA, it will probably take some waters from bulk and deform itself anyway. The gas phase is probably an approximation to the DNA solution... Then I would suggest to use harmonic positional restraints for selected atoms or torsional restraints for backbone, depending on what is technically more accessible to you. Finally, the interpretation of your results might be problematic in any case.
Dear Michal,
My first part of work is with the gas phase only.. I could't understand your previous reply(torsional restraints for backbone). Can you please explain me.
You may want not to allow the backbone to change its conformation. Freezing the atoms is probably quite strict. There are two meaningful ways how to keep the backbone arrangement: in Cartesian coordinates to use position restraints or better in internal coords to keep the dihedral angles within some "reasonable" range. It mostly depends on the code you use, what approach should be chosen. Here you can find some ideas:
http://www.gromacs.org/Documentation/How-tos/Position_Restraints
http://ambermd.org/Questions/constraints.html
http://x3dna.org/highlights/restraint-optimization-of-dna-backbone-geometry-using-phenix
There is a technique that allows rapid optimization DNA in the implicit water (not molecular dynamics at normal temperature). This is Sheffield model. Geometric results are not bad. (Of course, results in explicit water will be better but much slower)
Sheffield model is implemented in Ascalaph http://www.biomolecular-modeling.com/Products.html
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