Initial Aggregation and Ordering Mechanism of Diphenylalanine from Microsecond All-Atom Molecular Dynamics Simulations

Abstract

Self-assembled diphenylalanine (FF) nanostructures have recently been demonstrated to be interesting materials for antibacterial and anticancer applications. These applications, among others, seek to take advantage of the high-order and resulting appealing physical properties of FF nanostructures by modifying the peptide in some way to achieve specific functionality. To rationally design modifications to the dipeptide that allow for this behavior, the driving forces of FF self-assembly must be understood. Molecular simulations have been utilized to assess these properties but have yielded conflicting conclusions due to inconsistencies in models chosen as well as the lack of quantitative analyses on the specific driving forces. Here, we present an all-atom explicit solvent molecular dynamics-based study on different length scales of FF aggregation. We utilize a free energy decomposition analysis as well as a dimer cluster analysis to identify the initial aggregation driving force to be FF intermolecular electrostatics, whereas solvent-mediated forces drive crystal growth. These data are consistent with the hypothesis that all hydrophobic dipeptides will have a similar initial aggregation mechanism until a critical aggregate size is reached, at which point crystallization occurs and subsequent crystal growth is dominated by solvent-mediated forces. We demonstrate that this proposed mechanism is testable by infrared spectroscopy focusing on the blueshift of the amide I peak as well as the ordering of the carboxylate peak.

Implicit Solvation Using the Superposition Approximation (IS-SPA): Extension to Peptides in a Polar Solvent

“…The Lennard-Jones and Coulombic components of the free energy are computed separately in the IS-SPA framework and can be assessed from explicit solvent using a free energy decomposition scheme Figure b shows the Lennard-Jones component of the PMF, and Figure c shows the Coulombic component of the PMF.…”

“…The Lennard-Jones and Coulombic components of the free energy are computed separately in the IS-SPA framework and can be assessed from explicit solvent using a free energy decomposition scheme. 4 Figure 3b shows the Lennard-Jones component of the PMF, and Figure 3c shows the Coulombic component of the PMF. The oscillatory nature of the Lennard-Jones component is qualitatively captured by IS-SPA; both explicit (dashed lines) and IS-SPA (solid lines) demonstrate an attractive component for the Lennard-Jones component to the PMF of the negative ion (red) and a repulsive component to the PMF of the positive ion (blue).…”

“…Experimental approaches lack the multiscale resolution necessary to determine macroscopic structure, as well as the underlying molecular driving forces. All-atom molecular dynamics (aaMD) simulations have been employed to help elucidate the latter component. − However, aaMD cannot readily sample the large length- and time-scales necessary to capture macroscopic self-assembly. Additionally, these methods struggle with the low concentration of solutes typically used in peptide self-assembly experiments .…”

Organic biodegradable piezoelectric materials and their potential applications as bioelectronics

“…Diphenylalanine (FF), a peptide found in amyloid in Alzheimer's disease [29,30] , is a representative small molecule peptide with intriguing piezoelectric properties [31][32][33] . FF molecules can be self-assembled into various nano/microstructures in solutions through electrostatic forces, solvent-mediated force, -stacking or hydrogen bonding [34] . All-atom explicit solvent MD simulation has been performed to demonstrate that the driving force of FF nanotube formation was step dependent, in the sense that electrostatics was dominant .…”

Natural Piezoelectric Biomaterials: A Biocompatible and Sustainable Building Block for Biomedical Devices

“…The FF crystal has no inversion symmetry center with the space group P 6 1 that enables its piezoelectricity . The FF dipeptide can frequently self-assemble into nanowires and nanotubes structures driven by intermolecular hydrogen bonding, electrostatic force, solvent-mediated force, and π–π stacking. ,, Kholkin et al synthesized FF nanotubes that were assembled in pairs with oppositely directed polarizations (Figure a) . PFM measurements detected the in-plane signal along the tube axis, and uncovered its shear component of the piezoelectric coefficient ( d 15 ) from nanotube B.…”