Hydrophobic interactions and hydrogen bonds in \beta-sheet formation

TL;DR

This study uses molecular dynamics simulations to explore the driving forces behind eta-sheet formation in peptides, highlighting the roles of hydrophobic interactions and electrostatic energy rather than hydrogen bonds.

Contribution

It provides new insights into the microscopic mechanisms of eta-sheet formation, emphasizing the importance of hydrophobic interactions and electrostatics over hydrogen bonding.

Findings

eta-sheet conformations are favored at specific interpeptide distances.

Hydrogen bonds are not the main driving force for eta-sheet formation.

Electrostatic energy increases at short interpeptide distances.

Abstract

In this study, we investigate interactions of extended conformations of homodimeric peptides made of small (glycine or alanine) and large hydrophobic (valine or leucine) sidechains using all-atom molecular dynamics simulations to decipher driving forces for \beta-sheet formation. We make use of a periodic boundary condition setup in which individual peptides are infinitely long and stretched. Dimers adopt \beta-sheet conformations at short interpeptide distances (\xi ~ 0.5 nm) and at intermediate distances (~ 0.8 nm), valine and leucine homodimers assume cross-\beta-like conformations with side chains interpenetrating each other. These two states are identified as minima in the Potential of Mean Force (PMF). While the number of interpeptide hydrogen bonds increases with decreasing interpeptide distance, the total hydrogen bond number in the system does not change significantly, suggesting that formation of \beta-sheet structures from extended conformations is not driven by hydrogen bonds. This is supported by an increase in electrostatic energy at short interpeptide distances. A remarkable correlation between the volume of the system and the total electrostatic energy is observed, further reinforcing the idea that excluding water in proteins comes with an enthalpic penalty. We also discuss microscopic mechanisms accounting for \beta-sheet formation based on computed enthalpy and entropy and we show that they are different for peptides with small and large side chains.