temperature control for small molecule simulations in vacuum

From: Floris Buelens (floris_buelens_at_yahoo.com)
Date: Tue Jul 24 2007 - 06:50:01 CDT

Dear NAMD users,

I have some questions about the correctness of different temperature control methods for small molecules in vacuum, or decoupled from the surrounding environment. I'm trying to sample the free energy cost of confining a small molecule to a given region of space at a certain temperature, through multi-configuration thermodynamic integration: I have a set of restraints that define the area of space to which I want to confine my ligand, linked to a coupling factor; during the simulations I gradually scale up or down this coupling factor, and integrate the restraint energy as a function of the coupling factor. If anyone can comment in general whether this approach is feasible I'd be grateful, but I have a few specific questions:

- Is there a temperature control method that is particularly suited to this scenario? I started with Langevin dynamics but realised that the result changes with different values of the damping coefficient.
- More generally, how meaningful is the instantaneous or average temperature of a single molecule simulated in vacuum? If I have a molecule oscillating around a restraint, the instantaneous temperature will fluctuate accordingly... if the average temperature converges around my desired value, will I be measuring the desired quantity?
- How meaningful is any form of temperature control when considering a small molecule completely or almost completely decoupled from a surrounding protein-solvent system, as one would have in a FEP / TI simulation? Will any 'unnatural' behaviour from the small molecule be corrected by a thermostat that's monitoring the energy of the system as a whole?

Any more general insights into or alternative approaches to what I'm trying to do (sample the free energy cost in vacuum of applying a set of positional restraints from a standard state) would be very welcome indeed. Apologies for these very open-ended questions but I hope someone else has had to deal with them - many thanks for your time!

Best regards,

Floris Buelens
Department of Crystallography, Birbeck College, London

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