[GaMD-discuss] Peptide Gaussian Accelerated MD - Question about Simulation Set-up

[Arpan T. <agt...@nc...>]

Hello Prof Miao,

My name is Arpan Tapdiya, and I am a PhD student in Professor Carol Hall’s
research group in the Department of Chemical and Biomolecular Engineering
at North Carolina State University. Our group designs short peptides for
biosensor and therapeutic applications. To do so, we have developed our
Monte-Carlo based Peptide Binding Design Algorithm (PepBD), and we use
molecular dynamics (MD) and enhanced sampling to quantify peptide-target
interactions.

I am currently applying Pep-GaMD to study binding dynamics for our designed
10-residue peptides interacting with a ~240-residue protein target. I set
up simulations following the Pep-GaMD protocol from your paper
<https://doi.org/10.1063/5.0021399> (with a larger solvent box for this
system) and explored different boost settings, including varying σ0P and
σ0D from ~2 to 6 kcal/mol.

While the peptide behaves as expected by dissociating and exploring
bound/unbound regions, during the GaMD equilibration stage (when the boost
is applied to the target protein + solvent in the dual-boost scheme), the
target protein begins to lose its native secondary structure. The target
has four α-helices at the start of the simulation, but shortly after the
Gaussian boost is applied, it progressively unfolds and appears
intrinsically disordered. This occurs even at relatively small boost
settings. Notably, the system remains stable in conventional MD without the
GaMD boost.

The target structure is taken from the Protein Data Bank, and the peptide
was designed through our simulation workflow.

I would be very grateful for your guidance on the following:

   1.

   What are the most common causes of target protein unfolding in
   Pep-GaMD/GaMD runs?
   2.

   In your experience, can unfolding indicate that the boost potential is
   effectively too aggressive for the system even when σ0P/σ0D are set low? If
   so, what parameter adjustments or protocol changes would you recommend?
   3.

   Are there recommended strategies to maintain target stability in
   Pep-GaMD without adding additional constraints, while still allowing
   meaningful peptide binding/unbinding sampling?

If helpful, I can share the simulation setup details and the necessary
files.

Thank you very much for your time and for developing and sharing
GaMD/Pep-GaMD. This method is extremely valuable for the types of peptide
systems we study, and we will be thankful for any help!

Sincerely,
Arpan

-- 
Arpan Tapdiya
Graduate Student
Department of Chemical and Biomolecular Engineering
North Carolina State University