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Conformational Ensembles from Experimental Data
and Computer Simulations
Poster Abstracts
148
111-POS
Board 31
Improved GPCR Loop Structure Prediction by
Ab Initio
and Template-Based Sampling
with Triaxial Loop Closure
Jonghun Won
, Gyu Rie Lee, Chaok Seok.
Seoul National University, Seoul, South Korea.
Extracellular loops (ECLs), especially the second extracellular loop (ECL2), of G-protein-
coupled receptors (GPCRs) are often involved in GPCR functions. However, structure prediction
of ECL2 is more difficult than that of globular protein loops because of its long length.
Accordingly, several researchers have reported
ab initio
methods specialized for ECLs.
In this research, a new ECL2 structure prediction method that uses both
ab initio
and template-
based sampling is developed. Noting that ECL2 structures of related GPCRs are similar,
adequate structural templates are first detected among GPCRs with experimentally resolved
structures. The template loop structures are then attached to the framework structure and the
loops are closed by triaxial loop closure, an analytical loop closure method.
Ab initio
loop
sampling is also conducted using fragment assembly and triaxial loop closure. The proper
geometry of the conserved disulfide bridge between the third transmembrane helix and ECL2 is
maintained during sampling by applying triaxial loop closure. Final model structures are ranked
and selected by the GALAXY energy. Performance of this method was tested on ECLs of 28
GPCR subtypes with available experimental structures. The method showed outstanding
accuracy compared to other available
ab initio
methods such as CABS. This method can provide
an accurate loop structure or an ensemble of structures that may be used for further experimental
or computational studies related to GPCR function or molecular design targeting GPCR.