Abstract
The self-assembling propensity of amyloid peptides such as diphenylalanine (FF) allows them to form ordered, nanoscale structures, with biocompatible properties important for biomedical applications. Moreover, piezoelectric properties allow FF molecules and their aggregates (e.g., FF nanotubes) to be aligned in a controlled way by the application of external electric fields. However, while the behavior of FF nanostructures emerges from the biophysical properties of the monomers, the detailed responses of individual peptides to both temperature and electric fields are not fully understood. Here, we study the temperature-dependent conformational dynamics of FF peptides solvated in explicit water molecules, an environment relevant to biomedical applications, by using an enhanced sampling method, replica exchange molecular dynamics (REMD), in conjunction with applied electric fields. Our simulations highlight and overcome possible artifacts that may occur during the setup of REMD simulations of explicitly solvated peptides in the presence of external electric fields, a problem particularly important in the case of short peptides such as FF. The presence of the external fields could overstabilize certain conformational states in one or more REMD replicas, leading to distortions of the underlying potential energy distributions observed at each temperature. This can be overcome by correcting the REMD initial conditions to include the lower-energy conformations induced by the external field. We show that the converged REMD data can be analyzed using a Markovian description of conformational states and show that a rather complex, 3-state, temperature-dependent conformational dynamics in the absence of electric fields collapses to only one of these states in the presence of the electric fields. These details on the temperature- and electric-field-dependent thermodynamic and kinetic properties of small FF amyloid peptides can be useful in understanding and devising new methods to control their aggregation-prone biophysical properties and, possibly, the structural and biophysical properties of FF molecular nanostructures.
Highlights
Small, biocompatible peptides, such as amyloid-forming diphenylalanine (FF), have raised an increasing interest in both theoretical[1−5] and experimental[6−10] nanoscience studies for almost two decades
We generate and use new data from replica exchange molecular dynamics (REMD) simulations performed in the presence of external electric fields to probe the combined T-field- and E-field-dependent conformational dynamics of FF peptides (Figure 1).[3,4]
The presence of the external fields can induce rapidly and overstabilize a low-energy conformational state in one or more REMD replicas, leading to distortions of the underlying potential energy distributions observed at each temperature
Summary
Biocompatible peptides, such as amyloid-forming diphenylalanine (FF), have raised an increasing interest in both theoretical[1−5] and experimental[6−10] nanoscience studies for almost two decades. Amyloid FF peptides and their bioinspired nanoscale structures such as FF and nanotubes, nanospheres, or even nanorods[12] have led to a multitude of applications in biomedicine, nanoscience, and nanotechnology.[5,7,8,13] there are significant limitations to using FF-based nanomaterials, one of the main factors being the instability of FF nanotubes in solution (e.g., a major limitation hindering the development of FF nanotube-based biosensors or drug delivery systems) and the relative heterogeneity of the local, nm-scale structures formed by self-assembly of the FF peptides under various conditions, including but not limited to temperature, pH, and solvation.[9,10] To overcome such barriers it becomes important to understand and control the peptide self-assembly process.
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