Peptide-based hybrids such as peptide-polymer conjugates and lipopeptides are soft materials composed of covalently linked blocks of peptides and synthetic/natural polymers or lipids. Applications of such nanosystems are relevant in different items spanning from material science to biomedicine. Given their broad applicability, there is motivation to understand the molecular and macroscale structure, dynamics, and thermodynamic behavior exhibited by such materials. As a matter of fact, the preparation of bioinspired nanoparticles (NPs) with manifold functionalities requires the optimization of their structure, size, shape, surface area, chemical composition, solubility and local geometry. To this end, molecular simulation studies such as atomistic molecular dynamics and coarse-grained simulations will be carried out to obtain fundamental understanding of the self-assembling process of peptide-polymer conjugates and lipopeptides and prediction of the corresponding self-assembled structures.
The proposal will focus on the computational and experimental investigation of temperature- and pH-sensitive molecules such as:
1. peptide conjugates with synthetic polymers and polysaccharides;
2. lipopeptides;
3. cholic acid derivative-peptide/lipopeptide conjugates with antimicrobial activity.
Classical Molecular Dynamics (MD) and Coarse-Grained simulations as a function of pH and concentration will be carried out to characterize the self-assembly rearrangement of these systems, at molecular level. SAXS, DLS, AFM, electron microscopies (SEM, TEM and cryo-TEM), NMR, circular dichroism, fluorescence, rheology, will be jointly used to investigate and optimize size, shape, charge and mechanical properties of NPs. Finally, the toxicity and the interaction between cells and self-assemblies of the most promising NPs will be assessed.
The innovation of this proposal concerns a combined theoretical and experimental approach to design bioinspired soft materials potentially useful for applications in biomedicine. Atomistic molecular dynamics simulations will be carried out to obtain fundamental understanding of the molecular and macroscale structure, dynamics, and thermodynamic behavior exhibited by such materials. Furthermore, the prediction of structural details of NPs obtained by molecular dynamics simulations will help to optimize their size, shape, surface area, chemical composition, and local geometry. On the other hand, theoretical calculations will be useful to rationalize and clarify experimental results obtained by different techniques (TEM, SEM, AFM microscopies and SAXS) on the self-assemblies under investigation.
From a theoretical-computational point of view, there is the possibility to characterize for the first time at an atomic level of detail the self-assembly process leading to aggregates of different sizes and shapes. In fact, our preliminary data based on several MD simulations of ten molecules of lipopeptide suggested that the pH conditions, resulting in different protonation states in the molecule, can remarkably affect the shape of the aggregates.
In this project, we would extend such a set of data, using a different number of lipopeptides as well as increasing the number of independent MD simulations. In this regard, lipopeptides with different peptide sequences and alkyl chain length will be designed and synthesized to understand the assembly process and the factors that control it.
From an experimental point of view, this proposal aims at designing and preparing novel bio-material efficient as drug vehicles and with low toxicity. The innovative procedures of synthesis and the characterization of such complex nanosystems, which will be performed by many different approaches, require in fact joining together much diverse expertise. To this end skills including those related to colloidal systems, peptide synthesis and structural characterization, preparation of self-assembling polymers obtained with controlled radical polymerizations, will be properly combined to characterize NPs with unprecedented level of details. Furthermore, in order to shed light on the aggregation behavior of the systems composed of peptides, lipids and cholic acid derivatives, we plan to perform classical MD simulations as a function of pH and concentration.
Thanks to the combination of different expertise, the present research project is surely innovative, and could substantially contribute to the development of advanced technologies based on different NPs. The successful application of such technologies may also lead to breakthroughs in materials design and in the development of new nano-based products. The combination of the different research experience and skills of the partners will pave the way towards these ambitious goals.