Predicting Three-Dimensional
Structures of Transmembrane
Domains of β-Barrel Membrane Proteins
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Abstract
β-Barrel membrane proteins are found in the outer
membrane
of gram-negative bacteria, mitochondria, and chloroplasts. They are
important for pore formation, membrane anchoring, and enzyme activity.
These proteins are also often responsible for bacterial virulence.
Due to difficulties in experimental structure determination, they
are sparsely represented in the protein structure databank. We have
developed a computational method for predicting structures of the
transmembrane (TM) domains of β-barrel membrane proteins. Based
on physical principles, our method can predict structures of the TM
domain of β-barrel membrane proteins of novel topology, including
those from eukaryotic mitochondria. Our method is based on a model
of physical interactions, a discrete conformational state space, an
empirical potential function, as well as a model to account for interstrand
loop entropy. We are able to construct three-dimensional atomic structure
of the TM domains from sequences for a set of 23 nonhomologous proteins
(resolution 1.8–3.0 Å). The median rmsd of TM domains
containing 75–222 residues between predicted and measured structures
is 3.9 Å for main chain atoms. In addition, stability determinants
and protein–protein interaction sites can be predicted. Such
predictions on eukaryotic mitochondria outer membrane protein Tom40
and VDAC are confirmed by independent mutagenesis and chemical cross-linking
studies. These results suggest that our model captures key components
of the organization principles of β-barrel membrane protein
assembly