Author Archives: King Ifashe

The Experimentally Relevant Future of Molecular Dynamics: Lessons from the Annual Danish Workshop on Advanced Molecular Simulations

I recently had the opportunity to present part of my PhD work on molecular dynamics (MD) studies of engineered T Cell Receptors at the Annual Danish Conference on Advanced Molecular Simulations in Aarhus, Denmark. The meeting had an emphasis on membrane biophysics, multi- & mesoscale simulations, with keynotes focusing on connecting MD to experimental relevance.

What I mainly got from the keynotes, Weria Pezeshkian, Mohsen Sadeghi, Matteo Degiacomi, Lucie Delemotte, and Ilpo Vattulainen is that the community is shifting from from exploratory, proof-of-concept simulations towards more quantitative, decision-ready modelling. i.e., multiscale workflows that admit their limits, report uncertainties, and actually talk to experiments. There was a shared way of thinking about multiscale simulations by first getting the chemistry and thermodynamics right with atomistic or coarse-grained MD, be honest about kinetics at the mesoscale, and only then claim mechanisms for membranes and proteins in ways that can be checked against data.

Here are the main things I took away:

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A guide to fixing broken AMBER MD trajectory files and visualisations.

You’ve just finished a week-long molecular dynamics simulation. You’re excited to see what happened to your protein complex, so you load up the trajectory in VMD and… your protein looks like it’s been through a blender. Pieces are scattered across the screen, water molecules are everywhere, and half your complex seems to have teleported to the other side of the simulation box. This chaos is caused by periodic boundary conditions (PBC).

PBC

PBC is a computational trick that simulates bulk behaviour by treating your simulation box like a repeating tile. When a molecule exits one side, it immediately reappears on the opposite side. This works perfectly for physics as your protein experiences realistic bulk water behaviour.

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Making Peace with Molecular Entropy

I first stumbled upon OPIG blogs through a post on ligand-binding thermodynamics, which refreshed my understanding of some thermodynamics concepts from undergrad, bringing me face-to-face with the concept that made most molecular physics students break out in cold sweats: Entropy. Entropy is that perplexing measure of disorder and randomness in a system. In the context of molecular dynamics simulations (MD), it calculates the conformational freedom and disorder within protein molecules which becomes particularly relevant when calculating binding free energies.

In MD, MM/GBSA and MM/PBSA are fancy terms for trying to predict how strongly molecules stick together and are the go-to methods for binding free energy calculations. MM/PBSA uses the Poisson–Boltzmann (PB) equation to account for solvent polarisation and ionic effects accurately but at a high computational cost. While MM/GBSA approximates PB, using the Generalised Born (GB) model, offering faster calculations suitable for large systems, though with reduced accuracy. Consider MM/PBSA as the careful accountant who considers every detail but takes forever, while MM/GBSA is its faster, slightly less accurate coworker who gets the job done when you’re in a hurry.

Like many before me, I made the classic error of ignoring entropy, assuming that entropy changes that were similar across systems being compared would have their terms cancel out and could be neglected. This would simplify calculations and ease computational constraints (in other words it was too complicated, and I had deadlines breathing down my neck). This worked fine… until it didn’t. The wake-up call came during a project studying metal-isocitrate complexes in IDH1. For context, IDH1 is a homodimer with a flexible ‘hinge’ region that becomes unstable without its corresponding subunit, giving rise to very high fluctuations. By ignoring entropy in this unstable system, I managed to generate binding free energy results that violated several laws of thermodynamics and would make Clausius roll in his grave.

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