CiteULike: cactus simulation

Entropic contributions and the influence of the hydrophobic environment in promiscuous protein-protein association

Chia-En Chang — 2008-05-28T18:47:22-00:00

Proceedings of the National Academy of Sciences, Vol. 105, No. 21. (27 May 2008), pp. 7456-7461.

The mechanisms by which a promiscuous protein can strongly interact with several different proteins using the same binding interface are not completely understood. An example is protein kinase A (PKA), which uses a single face on its docking/dimerization domain to interact with multiple A-kinase anchoring proteins (AKAP) that localize it to different parts of the cell. In the current study, the configurational entropy contributions to the binding between the AKAP protein HT31 with the D/D domain of RII alpha-regulatory subunit of PKA were examined. The results show that the majority of configurational entropy loss for the interaction was due to decreased fluctuations within rotamer states of the side chains. The result is in contrast to the widely held approximation that the decrease in the number of rotamer states available to the side chains forms the major component. Further analysis showed that there was a direct linear relationship between total configurational entropy and the number of favorable, alternative contacts available within hydrophobic environments. The hydrophobic binding pocket of the D/D domain provides alternative contact points for the side chains of AKAP peptides that allow them to adopt different binding conformations. The increase in binding conformations provides an increase in binding entropy and hence binding affinity. We infer that a general strategy for a promiscuous protein is to provide alternative contact points at its interface to increase binding affinity while the plasticity required for binding to multiple partners is retained. Implications are discussed for understanding and treating diseases in which promiscuous protein interactions are used. 10.1073/pnas.0800452105

Rattling the cage: computational models of chaperonin-mediated protein folding

Jeremy England — 2008-05-26T04:25:38-00:00

Current Opinion in Structural Biology, Vol. 18, No. 2. (April 2008), pp. 163-169.

Chaperonins are known to maintain the stability of the proteome by facilitating the productive folding of numerous misfolded or aggregation-prone proteins and are thus essential for cell viability. Despite their established importance, the mechanism by which chaperonins facilitate protein folding remains unknown. Computer simulation techniques are now being employed to complement experimental ones in order to shed light on this mystery. Here we review previous computational models of chaperonin-mediated protein folding in the context of the two main hypotheses for chaperonin function: iterative annealing and landscape modulation. We then discuss new results pointing to the importance of solvent (a previously neglected factor) in chaperonin activity. We conclude with our views on the future role of simulation in studying chaperonin activity as well as protein folding in other biologically relevant confined contexts.

The lattice as allosteric effector: Structural studies of alphabeta- and gamma-tubulin clarify the role of GTP in microtubule assembly

Luke Rice — 2008-05-02T10:24:15-00:00

Proceedings of the National Academy of Sciences, Vol. 105, No. 14. (8 April 2008), pp. 5378-5383.

GTP-dependent microtubule polymerization dynamics are required for cell division and are accompanied by domain rearrangements in the polymerizing subunit, alpha-tubulin. Two opposing models describe the role of GTP and its relationship to conformational change in alpha-tubulin. The allosteric model posits that unpolymerized alpha-tubulin adopts a more polymerization-competent conformation upon GTP binding. The lattice model posits that conformational changes occur only upon recruitment into the growing lattice. Published data support a lattice model, but are largely indirect and so the allosteric model has prevailed. We present two independent solution probes of the conformation of alpha-tubulin, the 2.3 A crystal structure of gamma-tubulin bound to GDP, and kinetic simulations to interpret the functional consequences of the structural data. These results (with our previous gamma-tubulin:GTPgammaS structure) support the lattice model by demonstrating that major domain rearrangements do not occur in eukaryotic tubulins in response to GTP binding, and that the unpolymerized conformation of alpha-tubulin differs significantly from the polymerized one. Thus, geometric constraints of lateral self-assembly must drive alpha-tubulin conformational changes, whereas GTP plays a secondary role to tune the strength of longitudinal contacts within the microtubule lattice. alpha-Tubulin behaves like a bent spring, resisting straightening until forced to do so by GTP-mediated interactions with the growing microtubule. Kinetic simulations demonstrate that resistance to straightening opposes microtubule initiation by specifically destabilizing early assembly intermediates that are especially sensitive to the strength of lateral interactions. These data provide new insights into the molecular origins of dynamic microtubule behavior. 10.1073/pnas.0801155105