Multiscale simulations of environment-induced conformational transitions in peptides: folding, partitioning and aggregation
Theoretical Chemistry: Electronic Structure, Dynamics, Simulation
Final Report Abstract
In this collaborative project between our group and the Sayar group at Koc University we investigated environment-induced conformational transitions of peptides in a multiscale simulation framework. Such transitions are of immense importance for our understanding of nanostructure formation in materials science as well as biomedical applications (one example being the typical intrinsically disordered proteins that are involved in neurodegenerative diseases). We focused on three model peptides: (i) diphenylalanine (FF), which exhibits a conformational change upon aggregation or interaction with a hydrophilic/ hydrophobic interface, (ii) GALA and (iii) LK peptides, which both show helix/coil transitions that are affected by the surrounding media. Simulations on an atomistic level of resolution gave us very interesting microscopic insights into the environment-dependent folding/unfolding processes and transition mechanisms. They provided information about the driving forces which cause the influence of local environment on folding and subsequently aggregation. The atomistic data allowed us to compare directly with spectroscopic (SFG and IR) data, aiding the interpretation of the latter. For coarse grained (CG) models, reproducing the correct conformational response of a biopolymer to an environment change is a huge transferability challenge. In this project we have investigated which factors lead to transferability issues related to the coupling between peptide folding, environment changes (e.g. in pH), aggregation, interaction with interfaces, and partitioning between aqueous and hydrophobic media. The chosen model peptides allowed us to study the following aspects: (i) the importance of the properties of soft interfaces in CG models; (ii) the typical secondary structure-inducing auxiliary interactions and how to make them responsive to changes in the solvent environment; (iii) interface-induced folding from intrinsically disordered to α-helical states. We successfully devised coarse graining strategies that provided us with models for each of the three peptides. FF gave us interesting insights on the interplay of peptide/solvent and solvent/solvent interactions and the control of conformational behavior. Most importantly, we realized how important the local structural properties of soft hydrophobic interfaces are on the conformational response of biomolecules. These insights have stirred great interest in the coarse graining community because similar conformational transitions can happen upon interactions with microscopic interfaces such as growing fibrils or similar nanostructures. For the peptides based on EALA and LK sequences, we designed intramolecular interactions that induce αhelix formation and that could be fine-tuned in combination with suitable sidechain-sidechain or sidechain-interface interactions in such a way that a helix-coil equilibrium (and a shift in said equilibrium) was be correctly reproduced. We obtained generally applicable insights into the coarse graining process for such systems, into auxiliary interactions that induce folding, and also into the representability of folding intermediates and transition paths. From this project several new developments have emerged: the FF results have been an invaluable basis for simulations of other small hydrophobic FF-based peptides which form nanostructures and which are discussed as potential drug-delivery vehicles. Starting from LK and EALA–which both show intrinsically disordered (ID) states–we began to look more deeply into how the conformational equilibria of ID peptides can be characterized and more efficiently explored. We have also begun to systematically compare the conformational phase space sampled by atomistic and CG simulation models, in particular also the transition mechanisms between different states. The CG models for EALA from this project–which show remarkably different kinetic mechanisms–will serve as an starting point for mixed-resolution transition path sampling and for subsequent studies of CG dynamics.
Publications
- ”Sticky Water Surfaces: Helix-Coil Transitions Suppressed in Cell Penetrating Peptide at the Air-Water Interface”, J. Chem. Phys., 141, 22D517, 2014
D. Schach, C. Globisch, S. Roeters, S. Woutersen, A. Fuchs, C. Weiss, E. Backus, K. Landfester, M. Bonn, C. Peter, T. Weidner
(See online at https://doi.org/10.1063/1.4898711) - ”Tipping the Scale from Disorder to Alpha-helix: Folding of Amphiphilic Peptides in the Presence of Macroscopic and Molecular Interfaces”, Plos Computational Biology, 11, e1004328, 2015
C. Dalgicdir, C. Globisch, C. Peter, M. Sayar
(See online at https://doi.org/10.1371/journal.pcbi.1004328) - ”Representing environment-induced helix-coil transitions in a coarse grained peptide model”, Eur. Phys. J. Special Topics, 225, 14631481, 2016
C. Dalgicdir, C. Globisch, M. Sayar, C. Peter
(See online at https://doi.org/10.1140/epjst/e2016-60147-8)
