lectureBiomolecularModeling.pptVIP

Outline What is biomolecular modeling? Historical perspective Theory and experiments Protein characterization Computational successes Remaining challenges What is biomolecular modeling? Application of computational models to understand the structure, dynamics, and thermodynamics of biological molecules The models must be tailored to the question at hand: Schrodinger equation is not the answer to everything! Reductionist view bound to fail! This implies that biomolecular modeling must be both multidisciplinary and multiscale Historical Perspective 1946 MD calculation 1960 force fields 1969 Levinthal’s paradox on protein folding 1970 MD of biological molecules 1971 protein data bank 1998 ion channel protein crystal structure 1999 IBM announces blue gene project Theoretical Foundations Born-Oppenheimer approximation (fixed nuclei) Force field parameters for families of chemical compounds System modeled using Newton’s equations of motion Examples: hard spheres simulations (alder and Wainwright, 1959); Liquid water (Rahman and Stillinger, 1970); BPTI (McCammon and Karplus); Villin headpiece (Duan and Kollman, 1998) Experimental Foundations I X-ray crystallography Analysis of the X-ray diffraction pattern produced when a beam of X-rays is directed onto a well-ordered crystal. The phase has to be reconstructed. Phase problem solved by direct method for small molecules For larger molecules, sophisticated Multiple Isomorphous Replacement (MIR) technique used Current resolution below 2 \AA Protein crystallography Difficult to grow well-ordered crystals Early success in predicting alpha helices and beta sheets (Pauling, 1950s) Experimental Foundations II NMR Spectroscopy Nuclear Magnetic Resonance provides structural and dynamic information about molecules. It is not as detailed as X-ray, limited to masses of 35 kDa Distances between neighboring hydrogens are used to reconstruct the 3D structure using global optimization Proteins I Polypeptide chains made up of amino acid