Paper Citing NAMD - Abstract
Satpati, Priyadarshi; Simonson, Thomas
Conformational Selection by the aIF2 GTPase: A Molecular Dynamics Study of Functional Pathways
BIOCHEMISTRY, 51:353-361, JAN 10 2012
Archaeal initiation factor 2 (aIF2) is a GTPase involved in protein biosynthesis. In its GTP-bound, "ON" conformation, it binds an initiator tRNA and carries it to the ribosome. In its GDP-bound, "OFF" conformation, it dissociates from tRNA. To improve our understanding of the role of each conformational state in the aIF2 "life cycle", we start from the state immediately after GTP hydrolysis, ON:GDP:P-i (where P-i is inorganic phosphate), and consider the possible next steps on the pathway to the OFF:GDP product. The first possibility is P-i dissociation, leading to ON:GDP, which could then relax into OFF:GDP. We use molecular dynamics simulations to compute the P-i dissociation free energy and show that dissociation is highly favorable. The second possibility is conformational relaxation into the OFF state before P-i dissociation, to form OFF:GDP:P-i. We estimate the corresponding free energy approximately, 2 +/- 3.5 kcal/mol, so that this is an uphill or weakly downhill process. A third possibility is relaxation into another conformation, neither ON nor OFF. Indeed, a third, "MIXED" conformation was seen recently in a crystal structure of the aIF2:GDP:P-i complex. For this conformational state, P-i dissociation is weakly unfavorable, in contrast to the ON and OFF states. From this, we will deduce that if the MIXED:GDP complex is not too unstable, the ON:GDP:P-i -> MIXED:GDP:P-i transformation is a downhill process, which can occur spontaneously. This suggests that the MIXED state could be a functional intermediate.
