Protein Gating

Although secondary structure changes of proteins can not be modelled  in Martini, tertiary conformational changes are unrestricted and in principle realistic within the general approximations underlying the coarse-grained model.

mscl-haloA fine example is the gating process of the mechano-sensitive channel of large conductance, MscL. Both the wild-type Tb-MscL and its gain-of-function mutant V21D embedded in a solvated lipid bilayer have been simulated [1].  Putting the membrane under tension, the channels undergo significant conformational changes in accordance with an iris-like expansion mechanism, reaching a conducting state on a microsecond timescale. The most pronounced expansion of the pore has been observed for the V21D mutant, which is consistent with the experimentally shown gain-of-function phenotype of the V21D mutant. Due to the inhomogeneous pressure distribution around the protein [5], the mere shape change of the channel provides a large contribution to the gating energy [6]. The gating of a MscL channel embedded in a liposome has also been simulated [4] (see figure). In another series of papers the gating mechanism of MscL observed in the simulations has been coupled to experimental measurements, including EPR and FRET data [7] and IMSS [9]. The effect of lysolipids and alcohol on the gating efficiency has also been studied in joint computational-experimental efforts [8,10].

Other channel proteins that have been simulated with Martini include voltage-gated potassium channels [2], the voltage dependent anion channel (VDAC2) [12], the SecY and SecA channels [3,13], and aritifical channels based on DNA origami [11]. Most recently, we performed simulations of the novel class of mechanosensors belonging to the Piezo family [14], as well as the CorA transporter for which we unravelled an asymmetric gating mechanism [16].

Another remarkable study illustrating the power of the Martini model (in combination with Go-type elastic networks) is the discovery of an allosteric pathway in case of the SOD enzyme [15]. The Martini-based simulations show how mutations on one side of the protein affect the opening and closing of a lid at the other side, explaining a number of experimental observations.

  • [1] S. Yefimov, P.R. Onck, E. van der Giessen, S.J. Marrink. Mechanosensitive membrane channels in action. Biophys. J., 94:2994-3002, 2008.
  • [2] W. Treptow, S.J. Marrink, M. Tarek. Gating motions in voltage-gated potassium channels revealed by coarse-grained molecular dynamics simulations. JPC-B, 112:3277-3282, 2008.
  • [3] J.A. Lycklama a Nijeholt, M. Bulacu, S.J. Marrink, A.J.M. Driessen. Immobilization of the plug domain inside the SecY channel allows unrestricted protein translocation. J. Biol. Chem., 285:23747-23754, 2010.
  • [4] M. Louhivuori, H.J. Risselada, E. van der Giessen, S.J. Marrink. Release of content through mechano-sensitive gates in pressurized liposomes. PNAS, 107:19856-19860, 2010. open access
  • [5] O.H.S. Ollila, H.J. Risselada, M. Louhivuori, E. Lindahl, I. Vattulainen, S.J. Marrink. 3D Pressure distribution in lipid membranes and membrane-protein complexes. Phys. Rev. Lett., 102:078101, 2009.
  • [6] O.H.S. Ollila, M. Louhivuori, S.J. Marrink, I. Vattulainen. Protein shape change has a major effect on the gating energy of a mechanosensitive channel. Biophys. J., 100:1651-1659, 2011.
  • [7] E. Deplazes, M. Louhivuori, D. Jayatilaka, S.J. Marrink, B. Corry. Structural investigation of MscL gating using experimental data and coarse grained MD simulations. PLoS Comp. Biol. 8:e1002683, 2012. open access
  • [8] N. Mukherjee, M.D. Jose, J.P. Birkner, M. Walko, H.I. Ingólfsson, A. Dimitrova, C. Arnarez, S.J. Marrink, A. Koçer. The activation mode of the mechanosensitive ion channel, MscL, by lysophosphatidylcholine differs from tension-induced gating. FASEB J., 28:4292-4302, 2014
  • [9] A. Konijnenberg, D. Yilmaz, H.I. Ingólfsson, A. Dimitrova, S.J. Marrink, Z. Li, C. Vénien-­‐Bryan, F. Sobott, A. Koçer. Global structural changes of an ion channel during its gating are followed by ion mobility mass spectrometry. PNAS, 111:17170-17175, 2014. abstract
  • [10] M.N. Melo, C. Arnarez, H. Sikkema, N. Kumar, M. Walko, H.J.C. Berendsen, A. Kocer, S.J. Marrink, H.I. Ingólfsson. High-throughput simulations reveal membrane-mediated effects of alcohols on MscL gating. JACS, 139:2664–2671, 2017. open access
  • [11] V. Maingi, J.R. Burns, J.J. Uusitalo, S. Howorka, S.J. Marrink, M.S.P. Sansom. Stability and dynamics of membrane-spanning DNA nanopores. Nature Comm. 8:14784, 2017. open access
  • [12] S. Dadsena, S. Bockelmann, J.G.M. Mina, D.G. Hassan, S. Korneev, G. Razzera, H. Jahn, P. Niekamp, D. Müller, M. Schneider, F.G. Tafesse, S.J. Marrink, M.N. Melo, J.C.M. Holthuis, Ceramides bind VDAC2 to trigger mitochondrial apoptosis. Nature Commun. 10:1832, 2019. doi:10.1038/s41467-019-09654
  • [13] S. Koch, `M. Exterkate, C.A. López, M. Patro, S.J. Marrink, A.J.M. Driessen Two distinct anionic phospholipid-dependent events involved in SecA-mediated protein translocation. BBA-Biomembr. 1861, 183035, 2019. doi.10.1016/j.bbamem.2019.183035
  • [14] A. Buyan, C.D. Cox, J. Barnoud, J. Li, H.S.M. Chan, B. Martinac, S.J. Marrink, B. Corry. Piezo1 forms specific, functionally important interactions with phosphoinositides and cholesterol. Biophys. J. 119:1683-1697, 2020. doi.10.1016/j.bpj.2020.07.043
  • [15] P.C.T. Souza, S. Thallmair, S.J. Marrink, R. Mera-Adasme. An Allosteric Pathway in SOD1 Unravels the Molecular Mechanism of the G93A ALS-Linked Mutation. J. Phys. Chem. Letters, 10:7740-7744, 2019. doi.org/10.1021/acs.jpclett.9b02868
  • [16] M. Nemchinova, J. Melcr, T.A. Wassenaar, S.J. Marrink, A. Guskov. Asymmetric CorA Gating Mechanism as Observed by Molecular Dynamics Simulations. J. Chem. Inf. Model. 2021, online. doi.10.1021/acs.jcim.1c00261