Skip to main content
SpringerLink
Log in

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

  • Published:
The Journal of Membrane Biology Aims and scope Submit manuscript

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  • Affentranger R, Tavernelli I, Di Iorio EE (2006) A novel hamiltonian replica exchange md protocol to enhance protein conformational space sampling. J Chem Theory Comput 2(2):217–228

    Article  CAS  Google Scholar 

  • Almeida F, Opella S (1997) fd coat protein structure in membrane environments: structural dynamics of the loop between the hydrophobic trans-membrane helix and the amphipathic in-plane helix. J Mol Biol 270(3):481–495

    Article  CAS  PubMed  Google Scholar 

  • Anglin TC, Brown KL, Conboy JC (2009) Phospholipid flip-flop modulated by transmembrane peptides WALP and Melittin. J Struct Biol 168(1):37–52

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Baaden M, Marrink SJ (2013) Coarse-grain modelling of protein–protein interactions. Curr Opin Struct Biol 23(6):878–886

    Article  CAS  PubMed  Google Scholar 

  • Bereau T (2011) Unconstrained structure formation in coarse-grained protein simulations. Ph.D. thesis, Carnegie Mellon University

  • Bereau T, Bachmann M, Deserno M (2010) Interplay between secondary and tertiary structure formation in protein folding cooperativity. J Am Chem Soc 132(38):13,129–13,131

    Article  CAS  Google Scholar 

  • Bereau T, Deserno M (2009) Generic coarse-grained model for protein folding and aggregation. J Chem Phys 130(23):235,106

    Article  Google Scholar 

  • Bereau T, Deserno M, Bachmann M (2011) Structural basis of folding cooperativity in model proteins: insights from a microcanonical perspective. Biophys J 100(11):2764–2772

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Bereau T, Globisch C, Deserno M, Peter C (2012) Coarse-grained and atomistic simulations of the salt-stable cowpea chlorotic mottle virus (SS-CCMV) subunit 26–49: \(\beta \)-barrel stability of the hexamer and pentamer geometries. J Chem Theory Comput 8(10):3750–3758

    Article  CAS  Google Scholar 

  • Bereau T, Wang ZJ, Deserno M (2014) More than the sum of its parts: coarse-grained peptide–lipid interactions from a simple cross-parametrization. J Chem Phys 140(11):115,101

    Article  Google Scholar 

  • Bernstein FC, Koetzle TF, Williams GJ, Meyer EF, Brice MD, Rodgers JR, Kennard O, Shimanouchi T, Tasumi M (1977) The protein data bank. Eur J Biochem 80(2):319–324

    Article  CAS  PubMed  Google Scholar 

  • Bunker A, Dünweg B (2000) Parallel excluded volume tempering for polymer melts. Phys Rev E 63(1):016,701

    Article  Google Scholar 

  • Caffrey M (2003) Membrane protein crystallization. J Struct Biol 142(1):108–132

    Article  CAS  PubMed  Google Scholar 

  • DeLucas L (2009) Membrane protein crystallization, vol 63. Academic Press, San Diego

    Google Scholar 

  • de Planque MR, Greathouse DV, Koeppe RE, Schäfer H, Marsh D, Killian JA (1998) Influence of lipid/peptide hydrophobic mismatch on the thickness of diacylphosphatidylcholine bilayers. a 2H NMR and ESR study using designed transmembrane \(\alpha \)-helical peptides and gramicidin A. Biochemistry 37(26):9333–9345

    Article  PubMed  Google Scholar 

  • Fattal DR, Ben-Shaul A (1993) A molecular model for lipid–protein interaction in membranes: the role of hydrophobic mismatch. Biophys J 65(5):1795

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Filipe HA, Moreno MJ, Róg T, Vattulainen I, Loura LM (2014) How to tackle the issues in free energy simulations of long amphiphiles interacting with lipid membranes: convergence and local membrane deformations. J Phys Chem B 118(13):3572–3581

    Article  CAS  PubMed  Google Scholar 

  • Freddolino PL, Harrison CB, Liu Y, Schulten K (2010) Challenges in protein-folding simulations. Nature Phys 6(10):751–758

    Article  CAS  Google Scholar 

  • Freddolino PL, Park S, Roux B, Schulten K (2009) Force field bias in protein folding simulations. Biophys J 96(9):3772–3780

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Frishman D, Argos P (1995) Knowledge-based protein secondary structure assignment. Proteins: Struct Funct Bioinf 23(4):566–579

    Article  CAS  Google Scholar 

  • Gapsys V, Seeliger D, de Groot BL (2012) New soft-core potential function for molecular dynamics based alchemical free energy calculations. J Chem Theory Comput 8(7):2373–2382

    Article  CAS  Google Scholar 

  • Globisch C, Krishnamani V, Deserno M, Peter C (2013) Optimization of an elastic network augmented coarse grained model to study CCMV capsid deformation. PLoS One 8(4):e60,582

    Article  CAS  Google Scholar 

  • Grossfield A, Feller SE, Pitman MC (2007) Convergence of molecular dynamics simulations of membrane proteins. Proteins: Struct Funct Bioinf 67(1):31–40

    Article  CAS  Google Scholar 

  • Holt A, Rougier L, Réat V, Jolibois F, Saurel O, Czaplicki J, Killian JA, Milon A (2010) Order parameters of a transmembrane helix in a fluid bilayer: case study of a walp peptide. Biophys J 98(9):1864–1872

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Huang J, MacKerell AD Jr (2014) Induction of peptide bond dipoles drives cooperative helix formation in the (AAQAA)3 peptide. Biophys J 107(4):991–997

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Humphrey W, Dalke A, Schulten K (1996) VMD: visual molecular dynamics. J Mol Graph 14(1):33–38

    Article  CAS  PubMed  Google Scholar 

  • Im W, Brooks CL (2005) Interfacial folding and membrane insertion of designed peptides studied by molecular dynamics simulations. Proc Natl Acad Sci USA 102(19):6771–6776

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Im W, Brooks CL III (2004) De novo folding of membrane proteins: an exploration of the structure and NMR properties of the fd coat protein. J Mol Biol 337(3):513–519

    Article  CAS  PubMed  Google Scholar 

  • Ingólfsson HI, Lopez CA, Uusitalo JJ, de Jong DH, Gopal SM, Periole X, Marrink SJ (2014) The power of coarse graining in biomolecular simulations. Wiley Interdiscip Rev 4(3):225–248

    Google Scholar 

  • Jiang W, Roux B (2010) Free energy perturbation hamiltonian replica-exchange molecular dynamics (FEP/H-REMD) for absolute ligand binding free energy calculations. J Chem Theory Comput 6(9):2559–2565

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Kar P, Feig M (2014) Recent advances in transferable coarse-grained modeling of proteins. Adv Protein Chem Struct Biol

  • Kar P, Gopal SM, Cheng YM, Panahi A, Feig M (2014) Transferring the primo coarse-grained force field to the membrane environment: simulations of membrane proteins and helix–helix association. J Chem Theory Comput 10(8):3459–3472

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Killian JA (2003) Synthetic peptides as models for intrinsic membrane proteins. FEBS Lett 555(1):134–138

    Article  CAS  PubMed  Google Scholar 

  • Kim T, Im W (2010) Revisiting hydrophobic mismatch with free energy simulation studies of transmembrane helix tilt and rotation. Biophys J 99(1):175–183

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Kolb A, Dünweg B (1999) Optimized constant pressure stochastic dynamics. J Chem Phys 111(10):4453–4459

    Article  CAS  Google Scholar 

  • Limbach HJ, Arnold A, Mann BA, Holm C (2006) Espresso: an extensible simulation package for research on soft matter systems. Comput Phys Commun 174(9):704–727

    Article  CAS  Google Scholar 

  • Liu P, Huang X, Zhou R, Berne B (2006) Hydrophobic aided replica exchange: an efficient algorithm for protein folding in explicit solvent. J Phys Chem B 110(38):19,018–19,022

    Article  CAS  Google Scholar 

  • Liu P, Kim B, Friesner RA, Berne B (2005) Replica exchange with solute tempering: a method for sampling biological systems in explicit water. Proc Natl Acad Sci USA 102(39):13,749–13,754

    Article  CAS  Google Scholar 

  • Lundbæk JA, Collingwood SA, Ingólfsson HI, Kapoor R, Andersen OS (2010) Lipid bilayer regulation of membrane protein function: gramicidin channels as molecular force probes. J R Soc Interface 7(44):373–395

    Article  PubMed Central  PubMed  Google Scholar 

  • Lyman E, Ytreberg FM, Zuckerman DM (2006) Resolution exchange simulation. Phys Rev Lett 96(2):028,105

    Article  Google Scholar 

  • MacCallum JL, Bennett W, Tieleman DP (2008) Distribution of amino acids in a lipid bilayer from computer simulations. Biophys J 94(9):3393–3404

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Marassi FM, Opella SJ (2003) Simultaneous assignment and structure determination of a membrane protein from NMR orientational restraints. Protein Sci 12(3):403–411

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Monticelli L, Kandasamy SK, Periole X, Larson RG, Tieleman DP, Marrink SJ (2008) The martini coarse-grained force field: extension to proteins. J Chem Theory Comput 4(5):819–834

    Article  CAS  Google Scholar 

  • Monticelli L, Tieleman DP, Fuchs PF (2010) Interpretation of \(^2\)H-NMR experiments on the orientation of the transmembrane helix walp23 by computer simulations. Biophys J 99(5):1455–1464

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Mori T, Jung J, Sugita Y (2013) Surface-tension replica-exchange molecular dynamics method for enhanced sampling of biological membrane systems. J Chem Theory Comput 9(12):5629–5640

    Article  CAS  Google Scholar 

  • Mouritsen OG, Bloom M (1984) Mattress model of lipid–protein interactions in membranes. Biophys J 46(2):141–153

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Mu Y (2009) Dissociation aided and side chain sampling enhanced hamiltonian replica exchange. J Chem Phys 130(16):164,107

    Article  Google Scholar 

  • Neale C, Bennett WD, Tieleman DP, Pomès R (2011) Statistical convergence of equilibrium properties in simulations of molecular solutes embedded in lipid bilayers. J Chem Theory Comput 7(12):4175–4188

    Article  CAS  Google Scholar 

  • Neale C, Madill C, Rauscher S, Pomès R (2013) Accelerating convergence in molecular dynamics simulations of solutes in lipid membranes by conducting a random walk along the bilayer normal. J Chem Theory Comput 9(8):3686–3703

    Article  CAS  Google Scholar 

  • Noid W (2013) Perspective: coarse-grained models for biomolecular systems. J Chem Phys 139(9):090,901

    Article  CAS  Google Scholar 

  • Nymeyer H, Woolf TB, Garcia AE (2005) Folding is not required for bilayer insertion: replica exchange simulations of an \(\alpha \)-helical peptide with an explicit lipid bilayer. Proteins Struct Funct Bioinf 59(4):783–790

    Article  CAS  Google Scholar 

  • Okabe T, Kawata M, Okamoto Y, Mikami M (2001) Replica-exchange Monte Carlo method for the isobaric–isothermal ensemble. Chem Phys Lett 335(5):435–439

    Article  CAS  Google Scholar 

  • Paloncýová M, Berka K, Otyepka M (2012) Convergence of free energy profile of coumarin in lipid bilayer. J Chem Theory Comput 8(4):1200–1211

    Article  PubMed Central  PubMed  Google Scholar 

  • Paschek D, García AE (2004) Reversible temperature and pressure denaturation of a protein fragment: a replica exchange molecular dynamics simulation study. Phys Rev Lett 93(23):238,105

    Article  Google Scholar 

  • Periole X, Cavalli M, Marrink SJ, Ceruso M (2009) Combining an elastic network with a coarse-grained molecular force field: structure, dynamics and intermolecular recognition. J Chem Theory Comput 5:2531–2543

    Article  CAS  Google Scholar 

  • Piana S, Lindorff-Larsen K, Shaw DE (2011) How robust are protein folding simulations with respect to force field parameterization? Biophys J 100(9):L47–L49

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Sugita Y, Okamoto Y (1999) Replica-exchange molecular dynamics method for protein folding. Chem Phys Lett 314(1):141–151

    Article  CAS  Google Scholar 

  • Swendsen RH, Wang JS (1986) Replica Monte Carlo simulation of spin glasses. Phys Rev Lett 57(21):2607–2609

    Article  PubMed  Google Scholar 

  • Ulmschneider JP, Doux JP, Killian JA, Smith JC, Ulmschneider MB (2009) Peptide partitioning and folding into lipid bilayers. J Chem Theory Comput 5(9):2202–2205

    Article  CAS  Google Scholar 

  • Ulmschneider MB, Doux JP, Killian JA, Smith JC, Ulmschneider JP (2010) Mechanism and kinetics of peptide partitioning into membranes from all-atom simulations of thermostable peptides. J Am Chem Soc 132(10):3452–3460

    Article  CAS  PubMed  Google Scholar 

  • Ulmschneider MB, Ulmschneider JP (2008) Folding peptides into lipid bilayer membranes. J Chem Theory Comput 4(11):1807–1809

    Article  CAS  Google Scholar 

  • Venturoli M, Smit B, Sperotto MM (2005) Simulation studies of protein-induced bilayer deformations, and lipid-induced protein tilting, on a mesoscopic model for lipid bilayers with embedded proteins. Biophys J 88(3):1778–1798

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • von Heijne G (2011) Introduction to theme membrane protein folding and insertion. Annu Rev Biochem 80:157–160

    Article  Google Scholar 

  • Wan CK, Han W, Wu YD (2011) Parameterization of pace force field for membrane environment and simulation of helical peptides and helix–helix association. J Chem Theory Comput 8(1):300–313

    Article  Google Scholar 

  • Wang ZJ, Deserno M (2010) Systematic implicit solvent coarse-graining of bilayer membranes: lipid and phase transferability of the force field. New J Phys 12(9):095,004

    Article  Google Scholar 

  • Wang ZJ, Deserno M (2010) A systematically coarse-grained solvent-free model for quantitative phospholipid bilayer simulations. J Phys Chem B 114(34):11,207–11,220

    Article  CAS  Google Scholar 

Download references

Acknowledgments

We thank Zun-Jing Wang for her careful work parametrizing and implementing the lipid CG model, as well as early validation of the peptide–lipid cross-parametrization. We are also indebted to Cameron Abrams, Mike Allen, Frank Brown, Ed Lyman, and Alex Sodt, for constructive suggestions on our methodologies. We acknowledge Aoife Fogarty, Kurt Kremer, and Debashish Mukherji for critical reading of the manuscript. This work was partially funded by the Max Planck Institute for Polymer Research (TB) and NSF Grant MCB #1330226 (MD).

Author information

Authors and Affiliations

  1. Max Planck Institute for Polymer Research, Ackermannweg 10, 55128, Mainz, Germany

    Tristan Bereau

  2. Department of Physics, Carnegie Mellon University, Pittsburgh, PA, 15213, USA

    Markus Deserno

Authors
  1. Tristan Bereau
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Markus Deserno
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Tristan Bereau.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Bereau, T., Deserno, M. Enhanced Sampling of Coarse-Grained Transmembrane-Peptide Structure Formation from Hydrogen-Bond Replica Exchange. J Membrane Biol 248, 395–405 (2015). https://doi.org/10.1007/s00232-014-9738-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00232-014-9738-9

Keywords

Search

Navigation