Peptitlerde çevresel etkilerle yapısal geçişler

Proteins are fascinating molecular machines with their ability to fold into unique 3-dimensional structures identified as their native states. Despite their surprisingly robust folding capability, proteins and peptides exhibit a strong tendency to form ordered aggregates if the environmental conditions are correctly tuned. The amphiphilic nature of peptides plays an important role in enabling aggregation in aqueous environment or at interfaces and surfaces or by allowing peptides to penetrate through or aggregate in membranes. In many cases the aggregation or the interaction of a peptide with a hydrophobic/hydrophilic interface triggers a conformational change in the molecule, which is usually coupled to the partitioning of the hydrophobic/hydrophilic residues of the peptide. Well known examples of the interplay of conformational change and aggregation or partitioning at interfaces are the misfolding of proteins upon amyloid aggregation, or more generally the induction of higher beta-sheet content by aggregation or by the presence of an interface. In order to better understand and ultimately control structure formation in peptide aggregates and peptide-based materials, knowledge of the relevant interactions, driving forces, pathways and assembly mechanisms is essential. In this thesis we utilize molecular dynamics simulations to provide microscopic structural and thermodynamic insight into the interplay of folding, aggregation and partitioning in peptide based systems. In order to illustrate environment driven conformational change, the first model system we have focused on is phenylalanine dipeptide (FF). With its only two aminoacid long sequence, this molecule forms one-dimensional nanotubes, in which the molecules adopt a cis-like conformation unlike their preferred state in water. Here, by analyzing molecular dynamics simulations of FF in bulk water and cyclohexane/water interface, we demonstrate how the hydrophobic/hydrophilic interface triggers the trans-to-cis conformational change. Moreover, we demonstrate that even a molecular interface can lead to a similar conformational change, and discuss the similarities and differences between macroscopic and molecular interfaces. Next, in order to overcome the time and length scale barriers in observing aggregation of peptides in molecular simulations, we develop a coarse-grained (CG) model capable of representing the conformational behavior of FF. Our CG model is unique in its ability to capture the correct representation of the target molecule in two different environments. We show that correct representation of a structural change, such as a trans-to-cis conformational switch, relies on thermodynamic driving forces. Hence, a solvation free energy based tuning is required to capture the correct partitioning behavior. In the second study we switch to the LK peptide which is a designed synthetic molecule. We demonstrate how the interplay of hydrogen bonding, hydrophobic interactions, and electrostatics leads to an intrinsically disordered peptide. When isolated in bulk water it lacks a well defined secondary structure and only in the presence of a macroscopic or molecular interface its targeted $\alpha$-helical secondary structure can be realized. In the case of LK the presence of an interface leads to a population shift in the conformational phase space of the molecule. We also calculate the potential of mean force as a function of aggregate size and demonstate that in agreement with experimental findings tetramers of LK are the stable form in solution. Our findings highlight the challenges associated with the coupled nature of aggregation, folding and partitioning for peptides. We show that molecular dynamics simulations provide atomistic resolution analysis of the driving forces for such phenomena, perfectly complementing experimental techniques.