Bridging Molecular Timescales with MELD and Blue Waters Alberto Perez
We need to know protein structures to make new drugs DNA Protein sequence Protein structure Rational Drug Design
We need to know protein structures to make new drugs HARD EASY Expensive Time consuming Not always possible DNA Protein sequence Protein structure Rational Drug Design
Key challenge: develop computational tools to predict protein structures from sequence
A grand challenge in structural biology is predicting the 3D structure of a protein given the sequence 6 months of continuous sampling is not enough for even a simple protein Nguyen, H., Maier, J., Huang, H., Perrone, V. & Simmerling, C. J. Am. Chem. Soc. 136, 13959–13962 (2014).
Molecular Modeling is a computational grand challenge Perez, A., Morrone, J. A. & Dill, K. WIREs Comput Mol Sci 125, e1309 (2017).
Computational brute force will not solve these grand challenges When will we be able to fold larger proteins?
We developed MELD to scale to larger systems Perez, A., Morrone, J. A., Simmerling, C. & Dill, K. Curr. Opin. Struct. Biol. 36, 25–31 (2016). Perez, A., MacCallum, J. L., Coutsias, E. A. & Dill, K.. J. Chem. Phys. 143, 243143 (2015).
MD is the basis of our method • Sparse + data • Ambiguous • Noisy force field
I lost my keys in the beach
MELD uses a Bayesian inference approach to incorporate data into simulations force field MacCallum*, Perez*, & Dill, Proc. Natl. Acad. Sci. U.S.A. 112, 6985–6990 (2015).
We use Hamiltonian Replica Exchange to enhance sampling High Temperature / Vanishing Restraints Low Temperature / Strong Restraints
MELD performed high accuracy blind predictions of 3D structure experiment prediction Top cluster Å Å Å 95 residues 67 residues 68 residues Perez et al. Science Advances (2016)
Blue Waters is key for CASP — the structure prediction competition • 3 months — daily new targets • 200 competing groups and methods • Hundreds of proteins • Strict deadlines (some as short as 5-7 days) • We are the only physics-based methodology in CASP
BW’s team help indispensable during CASP • 30 GPU nodes per protein • Sparse communication between nodes • Helping with compilation of the OpenMM/MELD plugin
Beyond folding — binding and pathways rrlll rrrll rrlll rrrll 3 4 3 4 rllll rrrrl rllll rrrrl 7 9 7 9 17 22 16 rrrlr rrllr 19 lrlll lrrll rrrrr lllll rrrrr lllll 12 2 2 1 1 13 11 14 rrlrr rlllr lrrrl llrll rllrr rlrrr llrrl lllrl 20 15 21 18 10 8 10 8 llllr lrrrr llllr lrrrr 6 5 6 5 lllrr llrrr lllrr llrrr 1. Perez, A., Sittel, F., Stock, G. & Dill, K. J Chem Theory Comput 14, 2109–2116 (2018). 2. Morrone, J. A. et al. J Chem Theory Comput 13, 863–869 (2017). 3. Morrone, J. A., Perez, A., MacCallum, J. & Dill, K. J Chem Theory Comput 13, 870–876 (2017).
Don’t miss these posters for more details! Protein Folding of Nonthreadables James Robertson, Alberto Perez, Ken Dill Protein Structure Prediction Remains Important and Challenging Non- >SEQUENCE threadable ADPALADVCRTKLPSQAQDT LALIAKNGPYPYNRDGVVFE NRESRLPKKGNGYYHEFTVV TPGSNDRGTRRVVTGGYGEQ Threadable YWSPDHYATFQEIDPRC • Threading methods predict 86% of human protein structures, but many proteins are nonthreadable • MELD folds proteins fast, is physics- based, and not limited like threading • Can MELD fold nonthreadable proteins? MELD is an Accelerator for Molecular Simulations • MELD uses temperature and Hamiltonian replica exchange molecular dynamics (MD) to enhance conformational sampling and give free energies • MELD simulations run on GPU-accelerated supercomputers like NCSA Blue Waters MELD Folds Nonthreadable Proteins MELD Folder • MELD populations are predictor of folding MELD NonFolder • MELD is limited by force field deficiencies MELD Non-MELD MD Emiliano Brini james.robertson@stonybrook.edu @scijamesr James Robertson
Thanks! alberto.perez17@gmail.com
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