Enhanced Sampling of Coarse-Grained Transmembrane-Peptide Structure Formation from Hydrogen-Bond Replica Exchange

Abstract

Protein structure formation in the membrane highlights a grand challenge of sampling in computer simulations, because kinetic traps and slow dynamics make it difficult to find the native state. Exploiting increased fluctuations at higher temperatures can help overcome free-energy barriers, provided the membrane's structure remains stable. In this work, we apply Hamiltonian replica-exchange molecular dynamics, where we only tune the backbone hydrogen-bond strength to help reduce the propensity of long-lived misfolded states. Using a recently developed coarse-grained model, we illustrate the robustness of the method by folding different WALP transmembrane helical peptides starting from stretched, unstructured conformations. We show the efficiency of the method by comparing to simulations without enhanced sampling, achieving folding in one example after significantly longer simulation times. Analysis of the bilayer structure during folding provides insight into the local membrane deformation during helix formation as a function of chain length (from 16 to 23 residues). Finally, we apply our method to fold the 50-residue-long major pVIII coat protein (fd coat) of the filamentous fd bacteriophage. Our results agree well with experimental structures and atomistic simulations based on implicit membrane models, suggesting that our explicit CG folding protocol can serve as a starting point for better-refined atomistic simulations in a multiscale framework.

Folding and insertion thermodynamics of the transmembrane WALP peptide

“…27 More recently, the use of a Hamiltonian replica exchange algorithm (more below) assisted in folding several peptides inside the membrane: WALP{16,19,23}, as well as the 50-residue-long major pVIII coat protein (fd coat) of the filamentous fd bacteriophage. 28 …”

“…28 We ran all simulations with the ESPRS v3.4 molecular dynamics package. 55 A Langevin thermostat and modified Andersen barostat 56 produced an ensemble with constant temperature (T = 1.0 E/k B ), lateral tension (Σ = 0), and vertical box height.…”

“…In particular, we tuned the strength of the peptide's hydrogen-bond interaction, i.e., the prefactor ϵ of a modified Lennard-Jones potential with added directionality (see Appendix D). 28 The strength of the interaction was modulated by a prefactor λ, where λ ≥ 0. We ran HREMD simulations at prefactor values from λ = 0.1 to λ = 1.0, spanning an appropriate range of conformational space from fully helical to the complete absence of any helical motif.…”

“…28,31 Each simulation k corresponds to the Hamiltonian H k = H 0 + λV , where λ > 0. λ = 1 thus corresponds to the original Hamiltonian, H , while λ 1 alters the propensity to form hydrogen bonds.…”

“…Some of us reported similar findings using PLUM, a recently developed CG model, 27 with and without enhanced sampling. 28 In this last study, we demonstrated the model's ability to fold various peptides in a lipid bilayer, as the means to test whether the force field can describe simple aspects of peptidestructure formation, both in water and in a membrane environment. We also observed spontaneous insertion of WALP from water to the membrane.…”