Structure, dynamics and energetics of initiation sites in protein folding: I. Analysis of a 1 ns molecular dynamics trajectory of an early folding unit in water: the helix I/loop I-fragment of barnase.

The dynamic and energetic behavior of an initiation site of protein folding (helix I/loop I fragment of barnase) isolated from the tertiary environment of the rest protein is investigated in a 1 ns molecular dynamics simulation. All atom representation, explicit solvent description, and periodic boundary conditions are applied. In the course of the simulation several steps of structural disintegration are observed, followed by events partially rebuilding the initial structure. The phase of disintegration results in a fragment conformation completely lacking hydrogen bonds, with one residue in the center of the helix changed from alpha to beta conformation. The transition state of helix disintegration is characterized by a complete i-->i + 4/i + 5 hydrogen bonding network which undergoes gradual hydrolysis starting at the solvent exposed flank and proceeding towards the interior of the fragment perpendicular to the axis of the helix. Energetic analysis of the helix transitions shows that the i-->i + 4/i-->i + 5 network of hydrogen bonds accommodates one helical residue in beta conformation with only slightly worse hydrogen bonding energy and Van der Waals packing compared to the regular alpha-helix. The stability of the fragment is primarily due to hydrophobic interactions of residues shown to be essential in mutagenesis experiments.