Spontaneous Assembly of Functional Membrane Proteins from Soluble Membrane Active Peptides


Martin B. Ulmschneider, University of London


2017.10.16 14:00-15:00


601, Pao Yue-Kong Library


Experimental structural techniques have provided a wealth of molecular detail information on how proteins perform their functions in membranes. In contrast, little is currently known about functional structures and dynamics of pores that form only transiently in the membrane. This is chiefly due to a lack of technology that can capture transient structures in fluid membranes.

Here we demonstrate and experimentally validate a new methodology, based on unbiased long-timescale atomic detail equilibrium molecular dynamics simulations, that captures the entire assembly process of transient pores in lipid bilayers multiple times. This provides an unbiased and fully converged description of the assembly process.

Starting from unfolded peptides in water this approach predicts the insertion mechanisms and native state structures of membrane active peptides at atomic resolution, accurately reproducing experimental ensemble averages and partitioning data determined via synchrotron radiation circular dichroism spectroscopy and in vitro translocon experiments.

Once inserted peptides spontaneously assemble into functional channels in the bilayer that continuously form and disband. Remarkably, a single peptide is able to generate a large ensemble of functional pores of different sizes, lifetimes, and conductivities. This explains why, despite millions of years of co-evolution pore-forming peptides are still highly toxic to bacteria. The largest pore size was validated indirectly using a an assay that measures peptide-induced leakage of dyes encapsulated in vesicles. Finally, the approach is applied to attempt the design of novel functional peptides.


Dr. Ulmschneider graduated with a BA in Physics from Oxford University. He stayed at Oxford completing a DPhil on membrane protein simulations at the Laboratory of Molecular Biophysics. International fellowships from the Wellcome Trust, Human Frontiers, and the EU (Marie Curie) allowed him to work on membrane protein folding and membrane active peptides at the Indian Institute of Science in Bangalore, the University of Rome La Sapienza, Oxford University, Utrecht University, the University of California, Irvine, and Birkbeck College, London, before becoming an Assistant Professor at Johns Hopkins University working on biomaterials. He is currently a Reader (Associate Professor) at King’s College London working on membrane active peptide design for diagnostic and therapeutic applications.