Developing Computational Tools for the Study and Design of Amyloid Materials
Abstract
The self-assembly of short peptides into amyloid structures is linked to several diseases but has also been exploited for the design of novel functional amyloid-based materials. Such materials are potentially biocompatible and biodegradable, while their unique molecular organization provides them with remarkable mechanical properties. Amyloid fibrils are among the stiffest biological materials and exhibit a high resistance to breakage. Apart from the aforementioned properties, they are particularly attractive due to their easy synthesis and the ability to be redesigned through mutations at sequence level, which can result in potential functionality. Previous studies have reported the rational based design of functional amyloid materials, designed through primarily scientists’ intuition, and their applications in several fields as agents for tissue-engineering, antimicrobial and antibacterial agents, drug carriers, materials for separation applications, etc. The current work starts from the use of previously reported protocols for the computational elucidation of the structure of amyloids, leading to the formation of amyloid materials, and the investigation of the functional properties of rationally designed self-assembling peptides, and introduces a new approach for the computational design of functional amyloid materials, based on engineering and biophysical principles. In summary, we developed a computational protocol according to which an optimization-based design model is used to introduce mutations at non-βsheet residue positions of an amyloid designable scaffold (amyloid with non-β-sheet forming residues at its termini). The designed amino acids are introduced to the scaffold in such a way so that they mimic how amino acids bind to particular ions/compounds of interest according to experimentally resolved structures (defined by us as materialphore models) and also aim at energetically stabilizing the bound conformation of the pockets.
The optimum designs are computationally validated using a series of simulations and structural analysis techniques to select the top designed peptides, which are predicted to form fibrils with specific ion/compound binding properties for experimental testing. The computational protocol has been implemented first for the design of amyloid materials (i) binding to cesium ions, and in additional cases, for the design of amyloid materials (ii) serving as potential AD drug carriers, (iii) which could promote cell-penetration and possess DNA binding properties, and (iv) incorporating potential cell-adhesion, calcium and strontium binding properties. The computational protocol is also presented here as a step toward a generalized computational approach to design functional amyloid materials binding to an ion/compound of interest. This work can constitute a stepping stone for the functionalization of peptide/protein-based materials for several applications in the future.
Citation
Jonnalagadda, Sai Vamshi Reddy (2019). Developing Computational Tools for the Study and Design of Amyloid Materials. Doctoral dissertation, Texas A&M University. Available electronically from https : / /hdl .handle .net /1969 .1 /195905.