Inter-domain movements in polyketide synthases: a molecular dynamics studyElectronic supplementary information (ESI) available. See DOI: 10.1039/c2mb05425f

• Main Authors: Anand, Swadha, Mohanty, Debasisa
• Format: Article
• Language: English
• ISSN: 1742-206X; 1742-2051
• DOI: 10.1039/c2mb05425f

Insights into the structure and dynamics of modular polyketide synthases (PKS) are essential for understanding the mechanistic details of the biosynthesis of a large number of pharmaceutically important secondary metabolites. The crystal structures of the KSAT di-domain from erythromycin synthase have revealed the relative orientation of various catalytic domains in a minimal PKS module. However, the relatively large distance between catalytic centers of KS and AT domains in the static structure has posed certain intriguing questions regarding mechanistic details of substrate transfer during polyketide biosynthesis. In order to investigate the role of inter-domain movements in substrate channeling, we have carried out a series of explicit solvent MD simulations for time periods ranging from 10 to 15 ns on the KSAT di-domain and its sub-fragments. Analyses of these MD trajectories have revealed that both the catalytic domains and the structured inter-domain linker region remain close to their starting structures. Inter-domain movements at KSlinker and linkerAT interfaces occur around hinge regions which connect the structured linker region to the catalytic domains. The KSlinker interface was found to be more flexible compared to the linkerAT interface. However, inter-domain movements observed during the timescale of our simulations do not significantly reduce the distance between catalytic centers of KS and AT domains for facilitating substrate channeling. Based on these studies and prediction of intrinsic disorder we propose that the intrinsically unstructured linker stretch preceding the ACP domain might be facilitating movement of ACP domains to various catalytic centers. MD simulations on multi-domain polyketide synthases reveal inter- and intra-domain flexibility which can potentially facilitate channeling of substrates during polyketide biosynthesis.