- Last Updated: Friday, 23 April 2021 07:08
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.
A 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 . 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 , the mere shape change of the channel provides a large contribution to the gating energy . The gating of a MscL channel embedded in a liposome has also been simulated  (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  and IMSS . 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 , the voltage dependent anion channel (VDAC2) , the SecY and SecA channels [3,13], and aritifical channels based on DNA origami . Most recently, we performed simulations of the novel class of mechanosensors belonging to the Piezo family , as well as the CorA transporter for which we unravelled an asymmetric gating mechanism .
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 . 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.
-  S. Yefimov, P.R. Onck, E. van der Giessen, S.J. Marrink. Mechanosensitive membrane channels in action. Biophys. J., 94:2994-3002, 2008.
-  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.
-  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.
-  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
-  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.
-  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.
-  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
-  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
-  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
-  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
-  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
-  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
-  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
-  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
-  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
-  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