Conformational Sampling of Peptides in Cellular Environments

¹ University of Texas at Arlington
² Michigan State University

^* To whom correspondence should be addressed. E-mail: feig{at}msu.edu.

Submitted on June 27, 2007
Revised on July 29, 2007
Accepted on 13 September 2007

	Abstract

Biological systems provide a complex environment that can be understood in terms of its dielectric properties. High concentrations of macromolecules and co-solvents effectively reduce the dielectric constant of cellular environments, thereby affecting the conformational sampling of biomolecules. In order to examine this effect in more detail, the conformational preference of alanine dipeptide, poly-alanine, and melittin in different dielectric environments is studied with computer simulations based on recently developed generalized Born methodology. Results from these simulations suggest that extended conformations are favored over -helical conformations at the dipeptide level at and below dielectric constants of 5-10. Furthermore, lower-dielectric environments begin to significantly stabilize helical structures in poly-alanine at =20. In the more complex peptide melittin, different dielectric environments shift the equilibrium between two main conformations: a nearly fully extended helix that is most stable in low dielectrics and a compact, V-shaped conformation consisting of two helices that is preferred in higher dielectric environments. An additional conformation is only found to be significantly populated at intermediate dielectric constants. Good agreement with previous studies of different peptides in specific, less-polar solvent environments, suggest that helix stabilization and shifts in conformational preferences in such environments are primarily due to a reduced dielectric environment rather than specific molecular details. The findings presented here make predictions of how peptide sampling may be altered in dense cellular environments with reduced dielectric response.

Key Words: alanine dipeptide, continuum dielectric, implicit solvent, melittin, molecular dynamics, poly-alanine