Parameterization of novel molecules

1. Exotic Species

Most of your parameterization questions/problems can be resolved very simply, by remembering the following two rules:

You should not mix and match force fields. Force fields are (at best) designed to be self-consistent, and will not typically work well with other force fields. If you simulate part of your system with one force field and another part with a different force field which is not parameterized with the first force field in mind, your results will probably be questionable, and hopefully reviewers will be concerned. Pick a force field. Use that force field.
If you need to develop new parameters, derive them in a manner consistent with how the rest of the force field was originally derived, which means that you will need to review the original literature. There isn't a single right way to derive force field parameters; what you need is to derive parameters that are consistent with the rest of the force field. How you go about doing this depends on which force field you want to use. For example, with AMBER force fields, deriving parameters for a non-standard amino acid would probably involve doing a number of different quantum calculations, while deriving GROMOS or OPLS parameters might involve more (a) fitting various fluid and liquid-state properties, and (b) adjusting parameters based on experience/chemical intuition/analogy. Some suggestions for automated approaches can be found here.

It would be wise to have a reasonable amount of simulation experience with GROMACS before attempting to parameterize new force fields, or new molecules for existing force fields. These are expert topics, and not suitable for giving to (say) undergraduate students for a research project, unless you like expensive quasi-random number generators. A very thorough knowledge of Chapter 5 of the GROMACS Manual will be required. If you haven't been warned strongly enough, please read below about parameterization for exotic species.

Another bit of advice: Don't be more haphazard in obtaining parameters than you would be buying fine jewelery. Just because the guy on the street offers to sell you a "diamond" necklace for $10 doesn't mean that's where you should buy one. Similarly, it isn't necessarily the best strategy to just download parameters for your molecule of interest from the website of someone you've never heard of, especially if they don't explain how they got the parameters.

Be forewarned about using PRODRG topologies without verifying their contents: the artifacts of doing so are now published, along with some tips for properly deriving parameters for the GROMOS family of force fields.

Exotic Species

So, you want to simulate a protein/nucleic acid system, but it binds various exotic metal ions (ruthenium?), or there is an iron-sulfur cluster essential for its functionality, or similar. But, (unfortunately?) there aren't parameters available for these in the force field you want to use. What should you do? You shoot an e-mail to the GROMACS users emailing list, and get referred to the FAQs.

If you really insist on simulating these in molecular dynamics, you'll need to obtain parameters for them, either from the literature, or by doing your own parametrization. But before doing so, it's probably important to stop and think, as sometimes there is a reason there may not already be parameters for such atoms/clusters. In particular, here are a couple of basic questions you can ask yourself to see whether it's reasonable to develop/obtain standard parameters for these and use them in molecular dynamics:

Are quantum effects (i.e. charge transfer) likely to be important? (i.e., if you have a divalent metal ion in an enzyme active site and are interested in studying enzyme functionality, this is probably a huge issue).
Are standard force field parameterization techniques used for my force field of choice likely to fail for an atom/cluster of this type? (i.e. because Hartree-Fock 6-31G* can't adequately describe transition metals, for example)

If the answer to either of these questions is "Yes", you may want to consider doing your simulations with something other than classical molecular dynamics.

Even if the answer to both of these is "No", you probably want to consult with someone who is an expert on the compounds you're interested in, before attempting your own parameterization. Further, you probably want to try parameterizing something more straightforward before you embark on one of these.

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Parameterization of novel molecules

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Exotic Species

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