Justin Spiriti Zuckerman Lab MMBioS meeting 5/22/2014

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Presentation transcript:

Justin Spiriti Zuckerman Lab MMBioS meeting 5/22/2014 A New Strategy for Coarse-Grained Protein Simulations: Smoothed Energy Tables Justin Spiriti Zuckerman Lab MMBioS meeting 5/22/2014

Why novel coarse-grained methods? Coarse grained force fields Represent multiple atoms by a single particle Computational speedup from reduced number of particles Improved sampling from a smoother free energy surface Significant limitations Bias toward native structures/structures in the PDB Difficulties modeling secondary structures/charge distributions Lack of transferability Hard to adjust amount of coarse graining Previous work – Lettieri and Zuckerman, JCC 2012, 33, 268 Used smoothed energy tables to model benzene Achieved overall 114-fold speedup

Dividing amino acids into fragments Gly Ala Pro Arg Asn Asp Cys Gln Glu His+ Hisδ Ile Hisε Leu Lys Met Phe Ser Thr Trp Tyr Val Ace-Leu12-Nme (Leu12) GB1 hairpin

Interaction energy tables 6D interaction energy table for each pair of fragment types (sub-Å resolution) Use to compute energy in Monte Carlo simulations (r,θ,ϕ,ϕ’,θ’,ψ’) (r,θ,ϕ) (ϕ’,θ’,ψ’) Reference fragment configuration 2nd fragment θ ϕ r

Smoothing energy tables Convolve the Boltzmann factor e-βU with a Gaussian kernel function over the spherical angles (θ,ϕ) and the Euler angles (ϕ’,θ’,ψ’) Angular scale of Gaussian can be used to control degree of smoothing Association free energy of two fragments (related to second virial coefficient) unchanged by smoothing none 20° 40° 60° infinite Increasing smoothing

Leu12 with 60° smoothing

Preliminary results Leu12 vs. all-atom MD no tables Fraction α-helix speedup factor vs. MC w/o tables GB1 hairpin vs. all-atom MD no tables Fraction β-sheet speedup factor vs. MC w/o tables smoothing (°) smoothing (°) Speedup factor based on computational savings and improved sampling (as measured by increase in Ramachandran angle transition rates)

Future Directions Proteins as rigid fragments Use energy table for protein/protein interactions Preliminary work by Aaron van Dyne on barnase/barstar (TECBio 2013) Viral capsid assembly Incorporate into MCell to allow for electrostatics/protein shape/orientation dependent kinetics Continued work on molecular scale Improved smoothing/fragment shape preservation Better solvation methods Possible mixed resolution applications