(302c) Dock N' Roll, Templated Folding of a Silk-Inspired Beta-Solenoid

Self-assembling polymer-like polypeptides with stimulus responsive properties are used in biomedical applications including targeted delivery of nucleic acids for gene therapy, smart packaging, self-healing coating and biosensors. A polypeptide imitating the β-rich domain of Bombyx mori silk, which consists of (Gly-Ala-Gly-Ala-Gly-Ser) repeats, might be a promising candidate for use as one of the building blocks of these biomaterials due to its ability to self-assemble into filamentous structures. Atomistic molecular dynamics simulations are used to investigate a novel hydrophobic core β-roll (beta-solenoid) structure for the stacked building block in the structures formed by (GAGAGAGQ)_n. The hydrophobic core β-roll structure is composed of two oppositely oriented parallel β sheets that are connected by type II β turns. Our prediction of a type II β turn structure is in agreement with solid state NMR studies on the silk sequence (GA)₁₅, but differs from the  simulations-based prediction by Schor et al. (2009) for a highly similar sequence (GAGAGAGE)_n, which postulates a hydrophobic shell β-roll structure with type II’ β turns. Ground state analyses for both the hydrophobic core and hydrophobic shell structures for (GAGAGAGQ)_n, taking into account both the hydrophilic and hydrophobic interaction terms, show that because of solvation the hydrophobic core structure is more favorable than the hydrophobic shell structure. The stability of the hydrophobic core structure and hydrophobic shell β-roll structure are then compared using atomistic simulations with explicit water molecules. Despite the similarity between the dimensions of the two structures, the hydrophobic core structure is more thermodynamically stable than the hydrophobic shell structure. Accelerated molecular dynamics simulations have been carried out to sample more molecular conformations and draw the free energy landscape of the unfolding process for a β roll structure stacked on a fixed template. The hydrophobic core β roll structure is found to be the energetically favored structure associated with a prominent free energy minimum. A step-wise unfolding process is also observed.