Mechanisms and Energetics of Membrane Fusion

Collaborators: Reinhard Jahn, Neurobiology Department, MPI-NAT Göttingen; Marcus Müller, Department of Theoretical Physics, Soft Matter and Biophysics Group, University of Göttingen

Financial Support: Collaborative Research Center SFB 803 Functionality controlled by organization in and between membranes

Lipid membranes have rich physical properties and undergo a variety of conformational changes in the course of cellular processes. As part of a collaborative research center SFB 803, and in collaboration with the groups of Reinhard Jahn and Marcus Müller, we study these remodeling processes and how they are regulated by membrane proteins. A particular focus is on complex multi-step events, like synaptic and viral fusion, where the interplay of heterogeneous lipid compositions and regulatory proteins remains unclear. We use molecular dynamics (MD) simulations to resolve the physics governing these processes, with a special focus on the underlying quantitative energetic budgets –so-called free energy landscapes– and atomistic mechanisms.

Recent projects have studied isolated aspects of membrane fusion such as bending elasticity at extreme curvature [Bubnis et al., 2016], or the mechanism of aqueous pore nucleation. Other projects have addressed broader topics, like how the mechanical action of SNARE proteins controls the geometry and energetics of hemifusion stalk expansion [Risselada et al., 2014a], or how viral fusion proteins can trigger a 'leaky,' asymmetric fusion mechanism involving a stablized "stalk-pore" intermediate [Risselada et al., 2012a]. Coarse grained simulations and continuum models have also revealed that stable, nanometer-size "rim-pores" can form at the edges of hemifusion diaphragms [Risselada et al., 2012b, Risselada et al., 2014b].

A parallel focus is to develop novel enhanced sampling methods to access the high energy intermediate states (transition states) that connect the stable structures. One example is a permutation reduction scheme that preserves lipid sorting, minimally influencing ensemble properties, thereby enabling standard linear reaction coordinate biasing (i.e. umbrella sampling) for computing free energies [Bubnis et al., 2016]. Another method under development uses pore "gizmos" (artificial molecules) to help sample the transient topological intermediates between the open and closed pore states.

Risselada, H. J.; Grubmüller, H.: How proteins open fusion pores: insights from molecular simulations. European Biophysics Journal 50 (2), pp. 279 - 293 (2021)
Bubnis, G.; Risselada, H. J.; Grubmüller, H.: Exploiting lipid permutation symmetry to compute membrane remodeling free energies. Physical Review Letters 117 (18), 188102 (2016)
Risselada, H. J.; Bubnis, G.; Grubmüller, H.: Expansion of the fusion stalk and its implication for biological membrane fusion. Proceedings of the National Academy of Sciences of the United States of America 111 (30), pp. 11043 - 11048 (2014)
Risselada, H. J.; Marelli, G.; Fuhrmans, M.; Smirnova, Y. G.; Grubmüller, H.; Marrink, S. J.; Müller , M.: Line-tension controlled mechanism for influenza fusion. PLoS One 7 (6), e38302 (2012)
Risselada, H. J.; Grubmuller, H.: How SNARE molecules mediate membrane fusion: Recent insights from molecular simulations. Current Opinion in Structural Biology 22 (2), pp. 187 - 196 (2012)
Risselada, H. J.; Smirnova, Y.; Grubmüller, H.: Free energy landscape of rim-pore expansion in membrane fusion. Biophysical Journal 107 (10), pp. 2287 - 2295 (2014)
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