bridging molecular timescales with meld and blue waters
TRANSCRIPT
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
DNA Protein sequence Protein structure Rational Drug Design
EASY
Expensive Time consuming
Not always possible
HARD
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
Nguyen, H., Maier, J., Huang, H., Perrone, V. & Simmerling, C. J. Am. Chem. Soc. 136, 13959–13962 (2014).
6 months of continuous sampling is not enough for even a simple protein
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
force field
• Sparse
• Ambiguous
• Noisy
+ data
I lost my keys in the beach
MELD uses a Bayesian inference approach to incorporate data into
simulations
MacCallum*, Perez*, & Dill, Proc. Natl. Acad. Sci. U.S.A. 112, 6985–6990 (2015).force field
We use Hamiltonian Replica Exchange to enhance sampling
Low Temperature
High Temperature /
/ Strong Restraints
Vanishing Restraints
95 residues 67 residues 68 residues
MELD performed high accuracy blind predictions of 3D structure
Å Å ÅTop cluster
experiment prediction
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
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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).
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Don’t miss these posters for more details!
[email protected]@scijamesr
Protein Folding of Nonthreadables James Robertson, Alberto Perez, Ken Dill
Protein Structure Prediction Remains Important and Challenging
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
Threadable
Non- threadable
MELD Folds Nonthreadable Proteins
• MELD populations are predictor of folding• MELD is limited by force field deficiencies
>SEQUENCEADPALADVCRTKLPSQAQDTLALIAKNGPYPYNRDGVVFENRESRLPKKGNGYYHEFTVVTPGSNDRGTRRVVTGGYGEQYWSPDHYATFQEIDPRC
• 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
Non-MELD MD
MELD Folder
MELD NonFolder
Emiliano Brini
James Robertson
