Recent advances in maximum entropy biasing techniques for molecular dynamics

Abstract

This review describes recent advances by the authors and others on the topic of incorporating experimental data into molecular simulations through maximum entropy methods. Methods which incorporate experimental data improve accuracy in molecular simulation by minimally modifying the thermodynamic ensemble. This is especially important where force fields are approximate, such as when employing coarse-grain models, or where high accuracy is required, such as when attempting to mimic a multiscale self-assembly process. The authors review here the experiment directed simulation (EDS) and experiment directed metadynamics (EDM) methods that allow matching averages and distributions in simulations, respectively. Important system-specific considerations are discussed such as using enhanced sampling simultaneously, the role of pressure, treating uncertainty, and implementations of these methods. Recent examples of EDS and EDM are reviewed including applications to ab initio molecular dynamics of water, incorporating environmental fluctuations inside of a macromolecular protein complex, improving RNA force fields, and the combination of enhanced sampling with minimal biasing to model peptides.

Method for Accurately Predicting Solvation Structure

“…Alternatively, correction potentials can be fitted to minimise the error in the experimental properties such as the RDF. 52,53 This is obviously restricted to cases where accurate experimental data is available.…”

Using Cross‐Correlated Spin Relaxation to Characterize Backbone Dihedral Angle Distributions of Flexible Protein Segments

“…where β is a free parameter, often identified as “temperature”, balancing the contributions of χ 2 and the L2 penalty. This indirect way of entropy penalization is particularly suited for biasing techniques [22,69–71] that do not allow for explicit calculation of S . Its effect on the entropy can easily be assessed from Eq.…”

Steering Molecular Dynamics Simulations of Membrane-Associated Proteins with Neutron Reflection Results

“…Henceforth, in addition to exploring different settings of λ, we use ρ sim pr (z) both as a periodically updated instantaneous density or as a time averaged density that accumulates as the simulated trajectory extends. Polyalanine peptides (n = 15 and n = 35) were assembled in VMD, placed in a box of (88 Å) 3 and equilibrated in about 22,400 TIP3 water molecules in 100 mM NaCl under electrical neutrality using GROMACS by first minimizing energy in 50,000 simulation steps, followed by 50,000 simulation steps each in an NVT and an NPT ensemble, and completed with a 10 ns free simulation. An subsequent 10 ns MD run was then performed to create a mock experimental profile ρexp, and biased MD simulation runs started with the conformation at the end of this run.…”

“…Constrained computer simulations have been broadly used to identify models of molecular systems that are consistent with experimental observations. [1][2][3] In molecular dynamics (MD) simulations, biasing potentials usually achieve this by tilting the energy landscape such that molecular conformations which comply with known experimental outcomes are favored in the development of molecular trajectories. A variety of approaches are routinely used to align molecular models in MD with X-ray or NMR structures by adding a bias to the intermolecular forces that drive the MD computation engine.…”