Coarse-grained Models and Coarse-graining Techniques

Scott Carmichael Shell Group Presentation February 1, 2011

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Models
G Elastic Network Beads

Techniques
Reverse Monte Carlo Inverse Monte Carlo Boltzmann Inversion Iterative Boltzmann Inversion Force Matching

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G Models
Given a proteins native structure, develop a single bead per amino acid model whose structure is biased toward the native configuration by means of a simple attractive or repulsive non-bonded interactions between beads.

Pairs of residues feel a fictitious force towards their average separation distance.

Native state constitutes the minimum in the free energy landscape, such that the protein is perfectly relaxed, and there are no internal stresses. Folding free energy landscape is a smooth funnel, with the native state at the bottom. The concept is supported by the idea that proteins have evolved to minimize frustration when folding. Cannot explore non-native states, or mis-folded states with any degree of fidelity.

mdpi.com/1422-0067/10/3/889/

Elastic Network Models

Given the structure of a folded protein, develop a set of nodes connected by harmonic potentials such that the principle structure of the protein is represented by the nodal network.

The native contact topology determines spatial distribution of nodes.

Normal Mode Analysis (NMA) on the resultant model generally recovers accurate and informative principle modes.

Allostery can often be resolved, and in some cases transition state pathways identified as occurring along low frequency modes.

An online tool exists elNmo to generate these models. Hamiltonian:

E ij = K ij r ij r
i j

0 2 ij

mmb.pcb.ub.es/FlexServ/help/NMA.php

Bead Models
Given an amino acid residue sequence, make a coarse-grained model consisting of one or more interaction sites (beads) per amino acid.

Each type of bead shares the same interaction potential. Can be Toy models or all-atom based models.

Many different interaction motifs can be incorporated by different bead types: Polar, Hydrophobic, Charged, Neutral, etc. Beads typically have interaction potentials that include Bond, Angle, Torsional, and Pair interaction terms. The level of model detail is flexible because there are many ways to partition an amino acid residue into a given number of CG sites.

J. Chem. Phys. 126, 245104 (2007)

Reverse Monte Carlo

Given a target system's structure, generate the potential function that will regenerate the target systems structure.
A starting potential is used in a MC simulation to generate a RDF for the system. The RDF is then compared to the target system's RDF. The difference is then used to generate a modified potential and the scheme is iterated.

When the calculated and reference RDFs agree within the required limits, the potential can then be used to generate multiple configurations.

R L McGreevy 2001 J. Phys.: Condens. Matter 13 R877

Inverse Monte Carlo

Using linear response theory, estimate the correlation effects that a change in a given potential term will have on all other distribution functions. Then use this information to generation corrections to the CG potentials in an iterative fashion.

A susceptibility matrix,

P xU 1 M ' = R ; x ' R ; x ' U U ' x ' kBT

is used to solve the following equation for U ' :

P x= M ' x , x ' U ' x ' dx '

'

Boltzmann Inversion
Given a target system's probability distribution function for a given potential parameter argument, generate a potential function for that argument. The probability distribution for a potential argument (eg. P() for the bond angle) is populated using a target system ensemble.

The potential of mean force is then assumed to be the true potential.

Potential of Mean Force:

V q=k B T ln P q

V. Tozzini, J. A. McCammon, Chemical Physics Letters 413, 123-128 (2005)

Iterative Boltzmann Inversion

Given a target system's probability distribution function for a given potential parameter argument, generate a better potential function for that argument than BI will give you. A trajectory of a system that uses a BI derived potential will have a probability distribution that differs from that of the target system from which it was derived.

The difference between these two probability distribution functions can be incorporated into a correcting term used to refine the potential.

This procedure can be iterated using the following equation:

gi q V i1 q=V i qw i qk B T ln gtarget q

J. Ghosh, R. Faller, Molecular Simulation 33, 759 (2007)

Force Matching
Given an all atom trajectory, find a CG potential set that minimizes the difference between the CG system's forces and the all-atom system's mean force.

All-atom force information is obtained from simulation. A test CG force field is optimized by minimizing a force-matching functional defined as:

X = F F
l i

ref il

pred 2 il

Each term in the potential is expressed with a discrete set of basis functions. The basis function approach enables matrix solution methods to be utilized to minimize the functional directly.

S. Izvekov, G. A. Voth, The Journal of Physical Chemistry B 109, 2469-2473 (2005)

Thank you