Fibril–Barrel Transitions in Cylindrin Amyloids

Abstract

We introduce Replica-Exchange-with-Tunneling (RET) simulations as a tool for studies of the conversion between polymorphic amyloids. For the 11-residue amyloid-forming cylindrin peptide we show that this technique allows for a more efficient sampling of the formation and interconversion between fibril-like and barrel-like assemblies. We describe a protocol for optimized analysis of RET simulations that allows us to propose a mechanism for formation and interconversion between various cylindrin assemblies. Especially, we show that an interchain salt bridge between residues K3 and D7 is crucial for formation of the barrel structure.

Large Fatty Acid-derived Aβ42 oligomers Form Ring-like Assemblies

“…Derivation of these models relies on the computational techniques developed in the Hansmann lab. These methods have been already used in previous work to study the various polymorphs seen in amyloids [8][9][10][11] , and to probe the factors that modulate conformational switching in amyloids 11 . Combining computational investigations with novel biophysical experiments, we conclude that the 12mers prefer to form two-layered rings, each ring a hexamer (6 x 2), while 24mers transition to another species of two-layered assemblies, here each ring a dodecamer (12 x 2).…”

Multi-Funnel Landscape of the Fold-Switching Protein RfaH-CTD

“…Within this time interval, we observe an average exchange rate between neighboring replicas, with individual rates listed in table ST1, of 26 ± 3%, a value that is similar to the one seen by us in previous RET simulations where we also showed that regular Hamilton Exchange Replica Exchange let to lower rates (especially around λ = 0) if the same number of replica is used. 21,24,25 As a consequence, replica can walk on both sides of the ladder between replica with λ = λ max where the physical model is biased strongly by the corresponding Gomodel, and λ = 0 where the physical model is not biased by the Go-model. The number of walks between the two extreme values (called by us tunneling events) are a measure for the quality of simulation.…”

“…However, the exchange move between neighboring temperatures often leads to a proposal state that is exponentially suppressed, but if accepted the multiple replica system quickly relaxes to a state of comparable probability to that before the exchange. As a way to overcome this bottleneck and tunnel through the unfavorable transition we have recently introduced Replica-Exchange-with-Tunneling (RET) 21,24,25 by the following four-step-procedure:…”

“…Thus, in an effort to exploit the quick folding of Go models but remove in our simulations the associated bias against non-native folds, one can think of a Hamilton Replica Exchange Method 22 where at each replica a "physical" model is "fed" by a Go-model, but where the bias differs for each replica. 25,29,30 In the present implementation, the physical and the Go-model are coupled through a potential that depends on the similarity between configurations in the two models 30,31…”

“…21 We have shown that RET in conjunction with a Hamilton-Replica-Exchange 22,23 of systems where the "physical" system is coupled to varying degrees with biasing Go-models, allows efficient simulation of proteins and protein assemblies that can take more than one state. 24,25 For instance, we have used this approach in a a recent study 24 of the two mutants GA98 and GB98, which differ only in a single residues but keep the distinct original folds of the A and B domain of protein G, GA and GB. [26][27][28] We have shown how the mutation leading from GA98 to GB98 alters the energy landscape leading to selection of one fold over the other.…”