Article Understanding folding and design: Replica-exchange simulatio...

Normally, the fold and unfold changes are occured in ms, however, the classical MD simulations can hardly simulation so large time-scale, so you can try some special methods such as Replica-exchange simulations and Coarse-grained simulation

I would use our TIGER2h replica exchange method, which can save significant resources compared to classical REMD.

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"the allosteric regulator activates the enzyme throughout a large domain arrangement": does this mean you already have start and end structures of your enzyme? In other words, do you already have conformations of your enzyme before and after the allosteric ligand binds?

If this is the case, take a look at path-finding methods.

Check out this review: https://www.frontiersin.org/articles/10.3389/fmolb.2019.00117/full#h3

A coarse-grained pathway generation method: https://ebdims.biophysics.se/

If you wish to "sample the energy landscape of your protein" without specifying a target conformation, REMD and accelerated MD are good alternatives.

Thank you all for your kind suggestion

Yes Onur

I have both the structure starting and final conformations.

Thank you for the suggested paper.

can you suggest any other accelerated MD simulation references?

Aashish, sure. Note that "accelerated MD" as a method does NOT simulate transition from a starting conformation to a target conformation. It is rather an "enhanced sampling" method. Perhaps we should also clarify the difference between pure enhanced sampling methods aimed at "exploring" the free energy landscape of the protein and pathway-finding methods which simulate transitions between start and end conformations (hence, pathway generation). What you're looking for is therefore not "enhanced sampling", but "pathway-finding" methods.

What I would recommend is trying out the following alternatives (in addition to the eBDIMS server):

coMD (collective Molecular Dynamics): This is a practical method which can be combined with NAMD to generate transition pathways between start and target conformations of your enzyme. There's a tutorial available at: http://prody.csb.pitt.edu/tutorials/comd_tutorial/intro.html

Targeted Molecular Dynamics: NAMD offers features for simulating transitions between two conformations based on Targeted Molecular Dynamics method: https://www.ks.uiuc.edu/Research/namd/2.10b1/ug/node47.html

By the way, of course you can also generate "morphs" between two conformations of your enzyme by computing simple "deformation" vectors and generating conformations along these vectors. There are several servers which allow you to perform these "morphing" calculations. Take a look at the DynDom server, for example: http://dyndom.cmp.uea.ac.uk/dyndom/. Whether these morphs actually include real conformations that represent the conformational transition pathway between the two conformations is, of course, questionable, but they would nevertheless give you an idea on the underlying mechanism (calculation just takes minutes after all, no harm trying it out).

Thank you, Onur for giving a detailed answer.