Combining enhanced sampling with experiment-directed simulation of the GYG peptide

Abstract

Experiment directed simulation is a technique to minimally bias molecular dynamics simulations to match experimentally observed results. The method improves accuracy but does not address the sampling problem of molecular dynamics simulations of large systems. This work combines experiment directed simulation with both the parallel-tempering and parallel-tempering well-tempered ensemble replica-exchange methods to enhance sampling of experiment directed simulations. These methods are demonstrated on the GYG tripeptide in explicit water. The collective variables biased by experiment directed simulation are chemical shifts, where the set-points are determined by NMR experiments. The results show that it is possible to enhance sampling with either parallel-tempering and parallel-tempering well-tempered ensemble in the experiment directed simulation method. This combination of methods provides a novel approach for both accurately and exhaustively simulating biological systems.

Predicting chemical shifts with graph neural networks

“…CamShift uses a polynomial expansion of the pair-wise distances between an atom and its neighbors to approximate the NMR chemical shift 40 and thus is differentiable. This has made it a popular choice [41][42][43] and it is implemented in the PLUMED plugin 44 . However, CamShift does not treat side-chains and is insensitive to effects like hydrogen bonding.…”

Experimentally Consistent Simulation of Aβ21–30 Peptides with a Minimal NMR Bias

“…This peptide density was used to better replicate high peptide concentrations used in NMR experiments (0.5 mM in our experiments). We closely followed the method developed for using EDS with enhanced sampling described in Amirkulova and White …”

“…EDS is a type of maximum entropy technique which is used to incorporate experimental data into simulations. It is one of the many recent approaches to minimal biasing simulations to better match experimental data. ,,− A recent review of EDS can be found in the work by Amirkulova and White . Given a CV, f ( r⃗ ), EDS computes a potential energy bias U ′( r⃗ , f ( r⃗ )) and adds it to the potential energy of the whole system, U ( r ), such that the ensemble average of f ( r ) matches a chosen value: ⟨ f ( r )⟩ = f̅ .…”

“…Understanding Aβ peptide aggregation requires understanding its dynamics, and EDS has been shown to work well in improving thermodynamic accuracy while also maintaining or improving accuracy of dynamics . To address the large free energy barriers of peptide–peptide interactions, the enhanced sampling technique parallel tempering well-tempered ensemble (PT-WTE) was used. , PT-WTE was chosen because it requires an order of magnitude fewer replicas than parallel tempering simulations to achieve a comparable replica exchange efficiency …”

Editorial: “Introduction to the special issue on advanced molecular simulations: Methods and applications”

“…In this issue, Palmer and coworker discuss hybrid Monte Carlo/molecular dynamics (MC/MD) approach 4 and White and collaborators combine experiment directed simulation with parallel-tempering and parallel-tempering well-tempered ensemble replicaexchange methods. 5 Both methods overcome the limited sampling issues encountered in straightforward molecular dynamics simulations.…”