The broad, long-term objective of the proposed collaborative research is to articulate a microscopic basis for biomolecular folding codes. Recent tantalizing data from ultrafast T-jump experiments reported on proteins and DNA demonstrate the importance of separating events on the ultrashort time scale for solvation and folding. Data from ultrafast spectroscopy and multiple large-scale explicit water simulations will be interpreted with principal component analysis to provide a fresh perspective to the field. Our interest is in the relationship between water configurations and biomolecular structural change that occurs in less than the 100 picosecond regime. The immediate objective, however, is to examine the role of water in early folding events that may guide (slave) hydrophobic collapse to the native structure of proteins and DMA. Specific Aim 1: Initial water events for the folding of chicken villin headpiece subdomain. The fastest known ultrafast folding sequence, chicken villin headpiece subdomain (35-residues, VHS), will be studied using ultrafast experiments and computational all-atom simulations to provide a microscopic interpretation of folding. We propose to pay particular attention to the effects of solvent. Despite the extensive experimental and theoretical work reported on VHS, critical issues surrounding a microscopic understanding remain unanswered. Specific Aim 2: Construct a microscopic understanding of DNA folding and melting of a hairpin structure. The folding and melting kinetics of a 25 residue oligonucleotide hairpin structure has been reported using an ultrafast T-jump method. Three real-time events have been observed to include the timescales of water heating (<20 ps), double-strand destacking (700 ps to 2 ns), and loss of hairpin structure (greater than or equal to us). This experimental data has motivated us to pursue a microscopic interpretation to the role of water and ions on the three-state picture of melting and folding proposed by experiment. [unreadable] [unreadable] Public Statement: Advances in understanding how biological structures "fold" or attain their biochemical functional form will allow scientists and medical doctors cure diseases never considered possible before. [unreadable] [unreadable] [unreadable]