Computed Free Energies of Peptide Insertion into Bilayers are Independent of Computational Method
We show that the free energy of inserting hydrophobic peptides into lipid bilayer membranes from surface-aligned to transmembrane inserted states can be reliably calculated using atomistic models. We use two entirely different computational methods: high temperature spontaneous peptide insertion calculations as well as umbrella sampling potential-of-mean-force (PMF) calculations, both yielding the same energetic profiles. The insertion free energies were calculated using two different protein and lipid force fields (OPLS protein/united-atom lipids and CHARMM36 protein/all-atom lipids) and found to be independent of the simulation parameters. In addition, the free energy of insertion is found to be independent of temperature for both force fields. However, we find major difference in the partitioning kinetics between OPLS and CHARMM36, likely due to the difference in roughness of the underlying free energy surfaces. Our results demonstrate not only a reliable method to calculate insertion free energies for peptides, but also represent a rare case where equilibrium simulations and PMF calculations can be directly compared.
KeywordsPeptide partitioning Transfer free energy Translocon Membrane Molecular dynamics
J. C. G. acknowledges funding support from NSF (MCB-1452464) and NIH (R01-GM123169) and S. H. W acknowledges NIH support (RO1-GM74639). J. P. U. was supported by a China 1000 Plan's Program for Young Talents (13Z127060001). Simulation resources were provided by the Center for High Performance Computing, Shanghai Jiao Tong University and the Maryland Advanced Research Computing Center (MARCC). This work used the Extreme Science and Engineering Discovery Environment (XSEDE), which is supported by National Science Foundation grant number ACI-1548562. Anton computer time was provided by the Pittsburgh Supercomputing Center (PSC) through Grant R01GM116961 from the National Institutes of Health. The Anton machine at PSC was generously made available by D. E. Shaw Research.
Compliance with Ethical Standards
Conflict of interest
All authors declare they have no conflict of interest.
This article does not contain any studies with human participants or animals performed by any of the authors.
- Best RB, Zhu X, Shim J, Lopes PE, Mittal J, Feig M, MacKerell AD Jr (2012) Optimization of the additive CHARMM all-atom protein force field targeting improved sampling of the backbone φ, ψ and side-chain χ1 and χ2 dihedral angles. J Chem Theory Comput 8:3257–3273CrossRefPubMedPubMedCentralGoogle Scholar
- Feller SE, Zhang YH, Pastor RW, Brooks BR (1995) Constant pressure molecular dynamics simulations—the Langevin piston method. JCP 103:4613–4621Google Scholar
- Shaw DE, Dror RO, Salmon JK, Grossman JP, Mackenzie KM, Bank JA, Young C, Deneroff MM, Batson B, Bowers KJ, Chow E, Eastwood MP, Ierardi DJ, Klepeis JL, Kuskin JS, Larson RH, Lindorff-Larsen K, Maragakis P, Moraes MA, Piana S, Shan Y, Towles B (2009). Millisecond-scale molecular dynamics simulations on Anton. ACM/IEEE conference on supercomputing (SC09). ACM Press, PortlandGoogle Scholar