Abstract
Eukaryotic transmembrane helical (TMH) proteins perform a wide diversity of critical cellular functions, but remain structurally largely uncharacterized and their high-resolution structure prediction is currently hindered by the lack of close structural homologues. To address this problem, we present a novel and generic method for accurately modeling large TMH protein structures from distant homologues exhibiting distinct loop and TMH conformations. Models of the adenosine A2AR and chemokine CXCR4 receptors were first ranked in GPCR-DOCK blind prediction contests in the receptor structure accuracy category. In a benchmark of 50 TMH protein homolog pairs of diverse topology (from 5 to 12 TMHs), size (from 183 to 420 residues) and sequence identity (from 15% to 70%), the method improves most starting templates, and achieves near-atomic accuracy prediction of membrane-embedded regions. Unlike starting templates, the models are of suitable quality for computer-based protein engineering: redesigned models and redesigned X-ray structures exhibit very similar native interactions. The method should prove useful for the atom-level modeling and design of a large fraction of structurally uncharacterized TMH proteins from a wide range of structural homologues.
Highlights
Membrane proteins perform a wide diversity of critical functions in living cells but are involved in serious diseases and represent more than 60% of current drug targets [1,2]
The lack of high-resolution structures hinders the design of more effective therapeutics and of receptors with novel function for systems/synthetic biology applications which rely on atomic-resolution information [4]
High-resolution membrane protein structures are scarce which hinders the design of selective therapeutics and of receptors with novel function for systems/synthetic biology applications
Summary
Membrane proteins perform a wide diversity of critical functions in living cells but are involved in serious diseases and represent more than 60% of current drug targets [1,2]. The origins of TMH conformational diversity are multiple and range from the presence of localized sequence-specific distortions (e.g. Proline-induced kinks) to local bends and global tilts stabilized by specific tertiary contacts [18,19,20,21,22,23]. Many of these features cannot be accurately predicted from sequence information alone and requires the explicit modeling of atom-level physical interactions stabilizing these structures [18,19,20,24]. The large size of TM proteins and associated number of degrees of freedom combined with the ruggedness of the all-atom energy landscape make their prediction at atomic resolution computationally intractable using an exhaustive conformational search in torsional angle space
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