Multiscale Simulations of Self-Assembling Peptides: Surface and Core Hydrophobicity Determine Fibril Stability and Amyloid Aggregation.

Assemblies of peptides and proteins through specific intermolecular interactions set the basis for macroscopic materials found in nature. Peptides provide easily tunable hydrogen-bonding interactions, which can lead to the formation of ordered structures such as highly stable ß-sheets that can form amyloid-like supramolecular peptide nanofibrils (PNFs). PNFs are of special interest, as they could be considered as mimics of various fibrillar structures found in nature. In their ability to serve as supramolecular scaffolds, they could mimic certain features of the extracellular matrix to provide stability, interact with pathogens such as virions, and transduce signals between the outside and inside of cells. Many PNFs have been reported that reveal rich bioactivities. PNFs supporting neuronal cell growth or lentiviral gene transduction have been studied systematically, and their material properties were correlated to bioactivities. However, the impact of the structure of PNFs, their dynamics, and stabilities on their unique functions is still elusive. Herein, we provide a microscopic view of the self-assembled PNFs to unravel how the amino acid sequence of self-assembling peptides affects their secondary structure and dynamic properties of the peptides within supramolecular fibrils. Based on sequence truncation, amino acid substitution, and sequence reordering, we demonstrate that peptide-peptide aggregation propensity is critical to form bioactive ß-sheet-rich structures. In contrast to previous studies, a very high peptide aggregation propensity reduces bioactivity due to intermolecular misalignment and instabilities that emerge when fibrils are in close proximity to other fibrils in solution. Our multiscale simulation approach correlates changes in biological activity back to single amino acid modifications. Understanding these relationships could lead to future material discoveries where the molecular sequence predictably determines the macroscopic properties and biological activity. In addition, our studies may provide new insights into naturally occurring amyloid fibrils in neurodegenerative diseases.

Stable polydisperse free-standing porous films made by mechanical deformation.

Using molecular dynamics simulations, we show that the methodology of making thin stable nanoporous monodisperse films by biaxial mechanical expansion and subsequent cooling into the glassy state, also works for polydisperse films. To test this, a bidisperse polymer system of an equal number of very long (≈72 entanglements) and short (≤4 entanglements) chains with a polydispersity index of 1.80 is considered. The void formation and the development of the local morphology upon expansion, relaxation, and cooling are investigated. As for the monodisperse case, long chains in thin porous polydisperse films extend over several pores, stabilizing the whole morphology. The short chains do not fill up the pores but tend to aggregate inside the polymer matrix and to avoid surface areas and reduce conformational constraints imposed by the surrounding, a scenario very similar to strain-induced segregation between the strained long and relaxed short chains.

Entanglement-Stabilized Nanoporous Polymer Films Made by Mechanical Deformation.

We present a new simulation-guided process to create nanoporous materials, which does not require specific chemical treatment and solely relies on mechanical deformation of pure highly entangled homopolymer films. Starting from fully equilibrated freestanding thick polymer melt films, we apply a simple "biaxial expansion" deformation. Upon expansion holes form, which are prevented from growing and coalescing beyond a characteristic size due to the entanglement structure of the melt. We investigate the local morphology, the void formation upon expansion, and their stabilization. The dependence of the average void (pore) size and void fraction (porosity) on the total strain and subsequent relaxation is investigated. Furthermore, the stabilization of the porous structure of the thin expanded films through cooling below the glass transition temperature Tg is discussed.