Computational Experiments with a Lone-Pair Based Hydrogen-Bonding Energy Function in Mini-Rosetta YOUR NAME HERE (Arial 28 pt italic)YOUR PROJECT URL HERE.

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Computational Experiments with a Lone-Pair Based Hydrogen-Bonding Energy Function in Mini-Rosetta YOUR NAME HERE (Arial 28 pt italic)YOUR PROJECT URL HERE Acknowledgements : Kuhlman lab - Department of Biochemistry, UNC-CH Richardson lab - Duke University HERE Figure 2: Gary Bishop giving a head-mounted display demo to UNC System President Molly Broad. (Arial 24 pt italic) Rosetta is an ab-initio protein modeling program which includes a hydrogen-bond energy term. (Ref 1) Energy is a function of molecular geometry. Sum of independent terms (distance and two angles): Energy = F 1 (AH) + F 2 (BAH) + F 3 (AHD) where A : acceptor atom, B : base atom, H : proton, D : donor atom (Fig, 1) BAHD dihedral (in-plane constraint) not implemented. Hydrogen-bonds are divided into groups : helix, side-chain sp2, side-chain sp3, etc. and these groups are considered separately. Standard Hydrogen Bond Energy Function in Rosetta Fig. 1: Hydrogen Bonding Parameters used by Rosetta AH distance,  (BAH angle),  (DHA angle). X(BAHD dihedral) not implemented. Alternative: Lone-Pair Energy Function L2 B A D H L1 Different Parameters involving hydrogen docking sites - “lone pairs” - can we have an in-plane constraint without adding BAHD dihedral? (for computational efficiency, ease of visualization, etc.) Remove the independence assumption (couple parameters) - distance and two angles. Energy = F(AH, DHL, ALH ) where A : acceptor atom, H : proton, D: donor, L : lone- pair (docking site) (Fig. 2) Fit polynomial to 3-dimensional energy surface derived from database of 5200 protein structures. (Fig. 3) (starting with sp2 acceptor, side-chain hydrogen bonds) Future Directions Fig. 2 : Parameters for Lone Pair energy function. AH distance, DHL angle, ALH angle.  Extend potential to all hydrogen-bond types.  Re-weight hydrogen-bond term relative to other potentials.  Predict structures with new potential, compare to natives and to predicted structures developed using standard. Fig 3: Histogram (isosurfaces) based on lone-pair parameters for the sp2 acceptor, side-chain hydrogen bonds for the 5200 protein database. Fig. 4 : Histogram of BAHD dihedral for the 5200 protein set (native PDB structures). Note peak centered at 0°. (sp2 acceptor, side-chain hydrogen bond.) hydrogen bonds BAHD dihedral : Lone-Pair Energy Structure Improves Agreement with PDB structures Implement Lone-pair for sp2 acceptor side-chain hydrogen bonds. Run Monte Carlo/gradient optimizations (“classic relax”) with lone-pair and standard potentials. 28 protein set ( residues each) 10 relax runs for each protein. Examine BAHD dihedrals in relaxed structures - compare with native structures from the PDB. Methods Fig. 5 : Histogram of BAHD dihedral for structures relaxed with the standard potential for the 26 protein set (10 relaxed structures per protein) (sp2 acceptor, side-chain hydrogen bonds) 8316 hydrogen bonds. Fig. 6 : Histogram of BAHD dihedral for structures relaxed with the lone-pair potential for the 26 protein set (10 relaxed structures per protein) (sp2 acceptor, side-chain hydrogen bonds) 5738 hydrogen bonds. Christopher Sheldahl Snoeyink Lab Department of Computer Science, UNC-CH