Multiscale simulations of environment-induced conformational transitions in peptides: folding, partitioning and aggregation

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Peptides play an increasingly important role in various fields, from biomedical research, food science, to biomaterials applications. For example, amphiphilic peptides can be used for drug delivery purposes to help penetrate cell membranes. Here, an additional benefit is that peptides may be stimulus responsive, i.e. one can induce folding/unfolding by a change in pH or ion strength. Thanks to their proneness to form well-defined structured aggregates, peptides frequently serve as templates for biological and biomimetic materials. In order to systematically make use of peptides in a well-controlled manner, it is of immense importance to understand the relationship between sequence, secondary-structure formation, and the coupling of the folding to environmental conditions and to changes in the surrounding medium (pH, ion strength, hydrophilicity/ hydrophobicity, presence of an interface, presence of other peptides, etc.). Here, molecular simulation can provide microscopic understanding of the relevant interactions, solvation thermodynamics, etc. However, atomistic models alone are limited, and - in particular when aggregation phenomena are involved - coarse grained (CG) models are required to give access to the relevant system sizes and timescales.In order to provide a realistic representation of structure formation in peptide aggregates and peptide-based materials, the interplay of aggregation, folding and partitioning needs to be reflected in the CG model. This is a problem that can be viewed as a form of transferability challenge. Transferability refers to the issue that - due to the reduction of the number of degrees of freedom - CG models strongly depend on the state point (thermodynamic conditions, concentrations, chemical compositions etc.) where they were parameterized. This is one of the most severe limitations of CG models, which is the reason why the understanding and solving of transferability-related problems is one of the most important issues in the development of CG models.In this project we plan to develop transferable CG models for peptide-based biomaterials which are capable of reproducing the correct conformational behavior upon environment change. We plan to develop a strategy how to parameterize CG models that capture the coupling between and mutual influence of peptide folding, environment change such as pH or ion strength, aggregation, interaction with interfaces, and partitioning between aqueous and hydrophobic media. To this end, three target peptides were selected which allow to separately focus on different of the above aspects: (i) diphenylalanine exhibits a trans/cis conformational change upon aggregation or interaction with a hydrophilic/hydrophobic interface, while the (ii) GALA and (iii) KL peptides show a helix/coil transitions that are influenced by the surrounding media.