APS March Meeting 2017
Volume 62, Number 4
Monday–Friday, March 13–17, 2017;
New Orleans, Louisiana
Session F53: Biological Materials Self-Assembly
11:15 AM–2:15 PM,
Tuesday, March 14, 2017
Room: 287
Sponsoring
Units:
GSOFT DBIO
Chair: Jens Glaser Patrick Charbonneau, University of Michigan, Duke University
Abstract ID: BAPS.2017.MAR.F53.5
Abstract: F53.00005 : Ion transport across the biological membrane by computational protein design*
1:39 PM–2:15 PM
Preview Abstract
Abstract
Author:
Gevorg Grigoryan
(Dartmouth College)
The cellular membrane is impermeable to most of the chemicals the cell needs
to take in or discard to survive. Therefore, transporters---a class of
transmembrane proteins tasked with shuttling cargo chemicals in and out of
the cell---are essential to all cellular life. From existing crystal
structures, we know transporters to be complex machines, exquisitely tuned
for specificity and controllability. But how could membrane-bound life have
evolved if it needed such complex machines to exist first? To shed light
onto this question, we considered the task of designing a transporter de
novo. As our guiding principle, we took the ``alternating-access model''---a
conceptual mechanism stating that transporters work by rocking between two
conformations, each exposing the cargo-binding site to either the intra- or
the extra-cellular environment. A computational design framework was
developed to encode an anti-parallel four-helix bundle that rocked between
two alternative states to orchestrate the movement of Zn(II) ions across the
membrane. The ensemble nature of both states was accounted for using a free
energy-based approach, and sequences were chosen based on predicted
formation of the targeted topology in the membrane and bi-stability. A
single sequence was prepared experimentally and shown to function as a
Zn(II) transporter in lipid vesicles. Further, transport was specific to
Zn(II) ions and several control peptides supported the underlying design
principles. This included a mutant designed to retain all properties but
with reduced rocking, which showed greatly depressed transport ability.
These results suggest that early transporters could have evolved in the
context of simple topologies, to be later tuned by evolution for improved
properties and controllability. Our study also serves as an important
advance in computational protein design, showing the feasibility of
designing functional membrane proteins and of tuning conformational
landscapes for desired function.
*Alfred P. Sloan Foundation Research Fellowship
To cite this abstract, use the following reference: http://meetings.aps.org/link/BAPS.2017.MAR.F53.5