Roles of Hydrophobic Interactions and Hydrogen Bonds in Beta-Sheet Formation

Abstract

In this presentation, we will discuss interactions of extended conformations of homodimeric peptides made of small (glycine or alanine) and large hydrophobic (valine or leucine) sidechains using all-atom computer simulations to decipher driving forces behind beta-sheet formation. Dimers adopt beta-sheet conformations at short inter-peptide distances (x ∼ 0.5 nm) while at intermediate distances (∼ 0.8 nm), dimers made of valine or leucine assume “cross-beta like” conformations with sidechains interpenetrating each other. These two states are identified as minima in the Potential of Mean Force (PMF). While the number of inter-peptide hydrogen bonds increases with decreasing inter-peptide 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 confirmed by an increase in electrostatic energy at short inter-peptide distances. A remarkable correlation between the volume of the system and the total electrostatic energy is observed, supporting the view that excluded water regions in proteins have an enthalpic penalty. We will also discuss microscopic mechanisms accounting for beta-sheet formation based on computed enthalpy and entropy and we will show that they are different for peptides with small and large sidechains.