Conformational Ensembles from Experimental Data and Computer Simulations

Conformational Ensembles from Experimental Data and Computer Simulations

Poster Abstracts

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.

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