I have two all atom molecule dynamics systems of a protein. One is a wildtype and the other is a mutant. They differ by amino acid sequences. I am running my simulations in Gromacs. Each system has ran for 150 ns, showing certain system and physiological properties converging over the final 50 ns. Prior to this, each system will have gone through a series of short simulation steps where I relax position restraints on the protein and where I switch from the Berendsen pressure coupling to the Parrinello(sp?!) pressure coupling.
I am not entirely happy with sampling structural analysis from just one trajectory per system. My options could be:
1) Run the system for a lot longer and take results over a longer period of time, or,
2) Run triplicates per system; three for wildtype and three for mutant.
Taking three per system would involve three completely different sets of velocities, thus requiring the whole equilibrium procedure of relaxing through two different pressure coupling, relaxing position restraints on the protein etc... That's a lot of work all over again.
I was wondering whether it would be appropriate to take the final velocities from the system equilibrium step (just before I ran the 150 ns simulation, so I am talking about the final velocities from 1 ns where I have removing my position restraints from the protein backbone) and performing a 150 ns simulation, but the first 1 ns is a simulated annealing step of raising the temperature and then dropping it back down again.
My question: having used a set of preserved trajectories, by raising the temperature and then dropping back down, have I now accessed a new set of velocities and thus a different region or direction into conformational space, or will I simply shadow the earlier trajectory just a little sooner (having raised the temperature)?
I doubt a brief temperature spike will yield anything productive. Replicate simulations are the standard approach and are trivially easy to set up, just change the seed and re-use all existing inputs.
The best approach would be real replica exchange (temperature or Hamiltonian, though with the former you may be prone to unfolding, which would be unproductive), or some form of locally enhanced sampling (in AMBER, not GROMACS AFAIK).
I doubt a brief temperature spike will yield anything productive. Replicate simulations are the standard approach and are trivially easy to set up, just change the seed and re-use all existing inputs.
The best approach would be real replica exchange (temperature or Hamiltonian, though with the former you may be prone to unfolding, which would be unproductive), or some form of locally enhanced sampling (in AMBER, not GROMACS AFAIK).
Always something new to try! Thanks for confirming my suspicions regarding the temperature spike.
It's never very appropriate to heating up a protein system in MD. Normally you want to find the thermal equilibrium in NVT or NPT at T = 300 or 310 K. Your protein will unfold with increasing temperatures.
As the previous posters already pointed out, heating up a protein will lead the system to the ability of crossing energy barriers. Overcoming these energy barriers in the case of an already folded protein simply means denaturation. In-fact you would get some limited sampling of neighboring regions of that state BUT, and thats the important note: The respective state distribution is 1. Limited due even higher barriers that still exists 2. Not specific for a reasonable temperature for proteins.
Therefore, REMD is the method of choice. It enables to sample the conformational space, specific for a desired baseline temperature. Although it is computationally expensive, it's the most reliable choice of methods., especially the when using T-REMD imho, since there are no parmeters except of minmax temperatures and eventually the number of replicas.
If you wouldn't want the protein to unfold entirely, using a lower max temperature of e.g. 400K might restrict the conformationl space to only the molten globule area. This would also save replicas.
I highly advice to perform the REMD in explicit water. In this regards you migth be interested in alternative REMD methods such as TIGER2A. We currently have a own new method in review which is availbale soon hopefully.
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