title: Nucleotide Dependent Switching in Rho GTPase: Conformational Heterogeneity and Competing Molecular Interactions.
abstract: Ras superfamily of GTPases regulate myriad cellular processes through a conserved nucleotide (GTP/GDP) dependent switching mechanism. Unlike Ras family of GTPases, for the Rho GTPases, there is no clear evidence for the existence of "sub-states" such as state 1 &state 2 in the GTP bound form. To explore the nucleotide dependent conformational space of the Switch I loop and also to look for existence of state 1 like conformations in Rho GTPases, atomistic molecular dynamics and metadynamics simulations on RhoA were performed. These studies demonstrate that both the nucleotide-free state and the GDP bound "OFF" state have very similar conformations, whereas the GTP bound "ON" state has unique conformations with signatures of two intermediate states. The conformational free energy landscape for these systems suggests the presence of multiple intermediate states. Interestingly, the energetic penalty of exposing the non-polar residues in the GTP bound form is counter balanced by the favourable hydrogen bonded interactions between the γ-phosphate group of GTP with the highly conserved Tyr34 and Thr37 residues. These competing molecular interactions lead to a tuneable energy landscape of the Switch I conformation, which can undergo significant changes based on the local environment including changes upon binding to effectors.
authors.affiliation: Physical and Materials Chemistry Division, CSIR-National Chemical Laboratory, Pune 411008, India.
authors.forename: Amit
authors.initials: A
authors.lastname: Kumawat
authors.affiliation: Physical and Materials Chemistry Division, CSIR-National Chemical Laboratory, Pune 411008, India.
authors.forename: Suman
authors.initials: S
authors.lastname: Chakrabarty
authors.affiliation: Division of Biochemical Sciences, CSIR-National Chemical Laboratory, Pune 411008, India.
authors.forename: Kiran
authors.initials: K
authors.lastname: Kulkarni
mesh_terms: D000595:Amino Acid Sequence / Q000235:genetics; D001665:Binding Sites; D001667:Binding, Competitive; D006153:Guanosine Diphosphate / Q000737:chemistry; D006160:Guanosine Triphosphate / Q000737:chemistry; D056004:Molecular Dynamics Simulation; D011487:Protein Conformation; D020742:rhoA GTP-Binding Protein / Q000737:chemistry* / Q000235:genetics
chemical_list: D006153:Guanosine Diphosphate; D006160:Guanosine Triphosphate; D020742:rhoA GTP-Binding Protein