Subscriber access provided by Macquarie University
B: Biophysics; Physical Chemistry of Biological Systems and Biomolecules
Extension of the UNRES Coarse-Grained Force Field to Membrane Proteins in the Lipid Bilayer Karolina Zi#ba, Magdalena #lusarz, Rafa# #lusarz, Adam Liwo, Cezary Czaplewski, and Adam Kazimierz Sieradzan J. Phys. Chem. B, Just Accepted Manuscript • DOI: 10.1021/acs.jpcb.9b06700 • Publication Date (Web): 27 Aug 2019 Downloaded from pubs.acs.org on August 30, 2019
Just Accepted “Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted online prior to technical editing, formatting for publication and author proofing. The American Chemical Society provides “Just Accepted” as a service to the research community to expedite the dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully peer reviewed, but should not be considered the official version of record. They are citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or consequences arising from the use of information contained in these “Just Accepted” manuscripts.
is published by the American Chemical Society. 1155 Sixteenth Street N.W., Washington, DC 20036 Published by American Chemical Society. Copyright © American Chemical Society. However, no copyright claim is made to original U.S. Government works, or works produced by employees of any Commonwealth realm Crown government in the course of their duties.
Page 1 of 40 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
The Journal of Physical Chemistry
1
Extension of the UNRES Coarse-Grained Force Field to Membrane Proteins in the Lipid Bilayer 1 1 ´ ´ Karolina Zi¸eba1 , Magdalena Slusarz , Rafal Slusarz , Adam Liwo1 , Cezary Czaplewski1 ,
Adam K. Sieradzan,1,∗
1
Faculty of Chemistry, University of Gda´ nsk, Wita Stwosza 63, 80-308 Gda´ nsk, Poland
∗
Corresponding
author;
phone:
+48585235350;
[email protected] ACS Paragon Plus Environment
fax:
+48585235350;
e-mail:
The Journal of Physical Chemistry 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
Page 2 of 40
2
Abstract The physics-based UNRES coarse-grained force field for the simulations of protein structure and dynamics has been extended to treat membrane proteins. The lipid bilayer has been modeled by introducing a continuous nonpolar phase with the water-interface region of appropriate thickness. The potentials for average electrostatic and correlation interactions of the peptide groups have been rescaled to account for the reduction of the dielectric permittivity compared to the water phase and new potentials for protein side-chain – side-chain interactions inside and across the lipid phase have been introduced. The model was implemented in the UNRES package for coarse-grained simulations of proteins and the package with the new functionality was tested for total energy conservation and thermostat behavior in microcanonical and canonical molecular dynamics simulations runs, respectively. The method was validated by running unrestricted ab initio blind-prediction tests of 10 short α-helical membrane proteins, all runs started from the extended structures. The modified UNRES force field was able to predict correctly the overall folds of the membrane proteins studied.
ACS Paragon Plus Environment
Page 3 of 40 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
The Journal of Physical Chemistry
3
1
Introduction
Lipids are, along with proteins, polysaccharides and nucleic acids, one of most important components of the living cells. Lipids membranes perform many important functions in the living cells such as, e.g., keeping the cell shape, 1 maintaining the desired concentration of various components, 2,3 separation of various cellular organelles, 4 and protecting against pathogens. 5 All-atom simulations of proteins in lipid membranes are still limited to fairly small membrane samples and short time scales (tens of nanometers wide and at most a few hundred nanoseconds). 6,7 In particular, protein-membrane association and protein insertion into a membrane are computationally demanding with the use of all-atom approaches. Therefore coarse-grained approaches, in which several atoms are merged into larger pseudo-atoms, are used. 8–10 Of these coarse-grained approaches, the MARTINI force field, 9,11–13 in which each dimyristylphosphatocholine (DMPC) molecule is represented by 12 beads is the most widely used. MARTINI has been very successful in simulating the structure of lipid membranes and vesicles 9,11,13 as well as the dynamics of membrane proteins. 9,12,13 A version of MARTINI with water phase treated as a continuous phase (Dry MARTINI) has also been developed. 14 Despite the huge success of the MARTINI force field, it requires secondary-structures restraints for protein simulations. Recently, the highly successful CABS model of polypeptide chains 15 developed by the Koli´ nski group, was extended to treat membrane proteins by including a continuous representation of the lipid phase. 16 The UNited RESidue (UNRES) coarse-grained model of proteins that is being developed in our laboratory 17,18 is a highly reduced physics-based model, which has been very successful in physics-based prediction of protein structure, 19–21 studying the mechanisms and kinetics of protein folding, 22 as well as in investigating biological processes. 23,24 The presence of only two interaction sites (a united side chain and a united peptide group) per residue enables us to run simulations at time scales by 3-4 orders of magnitude longer compared to all-atom time scales, with reasonable accuracy, owing to the careful derivation of the expressions for the effective ACS Paragon Plus Environment
The Journal of Physical Chemistry 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
Page 4 of 40
4 energy function 25,26 through Kubo’s cluster-cumulant expansion 27 of the potential of mean force of a system under study in water. Membrane proteins in the lipid phase were not treated so far by the UNRES model. Therefore, in this paper, we have extended UNRES to introduce a continuous model of lipid bilayers. The force field has been revised to account for the transition of protein-chain components from the water phase to the lipid phase and for the interactions within and across the lipid phase. The new force field has been tested with small α-helical membrane proteins and was shown to produce structures reasonably close to the experimental structures in unrestricted simulations.
2
Methods
2.1
UNRES model of polypeptide chains
In the UNRES model, the geometry of a polypeptide chain is defined by the positions of the Cα atoms and those of the side-chains (SC) attached to them. The interaction sites are united peptide groups (p), each of which is located halfway between the two consecutive Cα atoms, and the united side chains. The positions of the Cα atoms are used only to define the geometry of the chain (Figure 1). The prototype of the UNRES force field is the potential of mean force of a protein in aqueous environment. In order to get an implementable energy function, the PMF is expanded into a Kubo cluster-cumulant series. 25,28 The complete effective energy function, which already includes mean-field interactions with the lipid phase, is expressed by eq 1.
ACS Paragon Plus Environment
Page 5 of 40 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
The Journal of Physical Chemistry
5
U = wSC
X
USCi SCj + wSCp
i
