1. Locating structural energy minima of biological molecules in explicit solvent APS March Meeting Baltimore 2006 Eric Dykeman Otto Sankey Arizona State University Department of Physics and Astronomy

2. E Local Minimum Barrier “Structural Energy Minima” Global Minimum One Dimensional Analogy Typically Molecules have many states that are stable corresponding to different folds or configurations of the atoms. The Goal  Locate all possible local minima of the molecule (states) starting from any stable local minimum.

3. Protein Misfolding Diseases Alzheimer's --- Mad Cow --- Type 2 Diabetes All believed to be caused by aggregation of specific peptides Peptides undergo a conformation change These new peptides then form fibril type masses which could be a source of the disease

4. E Soluble State Insoluble State Conformational Change Aggregation Theory Aggregation

5. Possible ways to search for other local minima MD TYPE METHODS Replica Exchange Molecular Dynamics **Reduce barrier analytically * Basic Idea Make Barrier easier to Traverse to a new local minimum During MD Simulation * **

6. Possible ways to search for other local minima ART Developed by Mousseu et.al. * Basic Idea Locate Barriers and Traverse to new local minimum via minimization Activation Relaxation Technique Barriers are located by examining the curvature of the energy hyper surface *

7. Moussue has shown ART to be an effective tool in searching for aggregation states in Alzheimer's Beta Amyloid Peptide * However, ART was originally designed for use with implicit solvation models and we wish to examine the possibility of extending ART to explicit solvent models. * How can ART be generalized?

8. One Idea for extending ART Separate the problem SYSTEM SolvantSolute MDART Maintain Solvent Thermodynamics Search for new molecular minima

9. Example System Alanine Dipeptide CH3-NH-CH3-CO-CH3 Ramachandran Plot of wet-ART predicted minima

10. Summary and Conclusions 1) Solvent adds temporary local minima. This effect may or may not be more pronounced in smaller molecules 2) Currently wet-ART on larger molecules has resulted in an unstable solvent due to molecule clashing with solvent