Comparing the Ability of Enhanced Sampling Molecular Dynamics Methods To Reproduce the Behavior of Fluorescent Labels on Proteins

Abstract

Adequately sampling the large number of conformations accessible to proteins and other macromolecules is one of the central challenges in molecular dynamics (MD) simulations; this activity can be difficult, even for relatively simple systems. An example where this problem arises is in the simulation of dye-labeled proteins, which are now being widely used in the design and interpretation of Förster resonance energy transfer (FRET) experiments. In this study, MD simulations are used to characterize the motion of two commonly used FRET dyes attached to an immobilized chain of polyproline. Even in this simple system, the dyes exhibit complex behavior that is a mixture of fast and slow motions. Consequently, very long MD simulations are required to sufficiently sample the entire range of dye motion. Here, we compare the ability of enhanced sampling methods to reproduce the behavior of fluorescent labels on proteins. In particular, we compared Accelerated Molecular Dynamics (AMD), metadynamics, Replica Exchange Molecular Dynamics (REMD), and High Temperature Molecular Dynamics (HTMD) to equilibrium MD simulations. We find that, in our system, all of these methods improve the sampling of the dye motion, but the most significant improvement is achieved using REMD.

Protonation state of inhibitors determines interaction sites within voltage-gated sodium channels

“…To best study the likely binding sites of local anesthetics in the sodium channel, we used REST2 (45) as implemented in NAMD (46). Replicaexchange methods have been shown to more efficiently improve conformational sampling than alternative methods such as metadynamics or accelerated MD (34,46,47), and the solute tempering method allows the approach to be used efficiently in large systems. To show that replica exchange solute tempering (REST) simulations indeed increase sampling of a compound in the pore, we chose a test system that has been well-characterized in simulation: the structure of NavAb [Protein Data Bank (PDB) ID code 3rvy] with benzocaine inside the pore (34)(35)(36), embedded in a pure 1-palmitoyl-2-oleoylphosphatidylcholine (POPC) bilayer.…”

Temperature-induced collapse of a disordered peptide observed by three sampling methods in molecular dynamics simulations

“…There are numerous studies applying enhanced sampling methods, but much fewer studies on the direct comparison between conformational ensembles of IDPs generated by different enhanced sampling techniques. [3][4][5][6] In this study, we generated the conformational ensembles of a polyglutamine (polyQ) 15-mer, Q15, over a wide range of temperatures in explicit solvent using cMD and two enhanced sampling methods, temperature replica exchange (TREMD) [7][8][9] and replica exchange with solute tempering (REST). [10][11][12][13][14] To our knowledge, this is the first time that REST was tested for its effectiveness at producing temperature-dependent properties of IDPs.…”

Dynamics of Fluorescent Dyes Attached to G‐Quadruplex DNA and their Effect on FRET Experiments

“…To overcome this limitation, replica-exchange MD (REMD) simulations [26] were conducted to better quantify the mostlikely locations of the dyes, because this method yields much betterconformational sampling than equilibrium simulations. [27] In addition REMD was combinedw ith metadynamics to further improve the sampling of the short-linker dyes( see the Experimental Section). The REMD simulations are indicatedb y the subscriptrin the following.…”

“…This can only be done accurately if the value of the bias potential does not change, and so the simulation was divided into two sections. [27] In the first, the bias was collected to speed conformational sampling. In the second, the bias was held constant to determine the relative probability of each conformation.…”