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

[Carol K H. <ha...@nc...>]

Hi Yinglong,

  Thanks for getting back to Arpan, It would be great  if you could look 
at our approach and give us some guidance. Would you be  amenable, 
perhaps , to talking with us in next week  or so and to chat?

I hope that  you are not too impacted by the weather situation . I just 
saw a few snowflakes.

Best wishes,

Carol


On 1/30/2026 4:52 PM, Miao, Yinglong wrote:
> Hi Arpan,
>
> Thanks for your interest in Pep-GaMD!
>
> Yes, it would be great if you can share your simulation input 
> parameter files and probably mdout file for the Pep-GaMD 
> equilibration. We can then look into the issue in more detail.
>
> Best regards,
> Yinglong
>
> Yinglong Miao, Ph.D.
> Associate Professor
> Department of Pharmacology
> Computational Medicine Program
> Lineberger Comprehensive Cancer Center
> University of North Carolina - Chapel Hill
> Tel: 1-919-962-5696
> http://miaolab.org
>
> Editor-in-Chief
> /npj Drug Discovery/
> https://www.nature.com/npjdrugdiscov
>
>> On Jan 30, 2026, at 11:02 AM, Arpan Tapdiya <agt...@nc...> wrote:
>>
>> 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
>
-- 
Carol K. Hall, Worley H. Clark, Jr. Distinguished University Professor
Department of Chemical and Biomolecular Engineering
North Carolina State University
Raleigh, North Carolina 27695-7905, USA
919-515-3571(phone);ha...@nc...
https://carolkhall.wordpress.ncsu.edu