Advanced

Simulation of proteins in crowded environments using coarse-graining methods

Linse, Björn LU (2016) PHYM01 20151
Computational Biology and Biological Physics
Department of Physics
Abstract
Of increasing interest in the field of protein modelling and simulation is the effects of crowding. In a living cell, large molecules can take up 30% of the cell plasma volume, and affects the folding and dynamics of proteins. Computer simulations have so far focused mainly on simple spherical crowders, but recent simulations with protein crowders have shown effects beyond what can be replicated using spherical crowders. However, this is a computational challenge as crowder proteins are much bigger than the protein under actual interest (target), and so simulation time will be dominated by updates of the crowders rather than the target.

In this thesis, based of an existing all-atom protein model with an empirical force field, we will... (More)
Of increasing interest in the field of protein modelling and simulation is the effects of crowding. In a living cell, large molecules can take up 30% of the cell plasma volume, and affects the folding and dynamics of proteins. Computer simulations have so far focused mainly on simple spherical crowders, but recent simulations with protein crowders have shown effects beyond what can be replicated using spherical crowders. However, this is a computational challenge as crowder proteins are much bigger than the protein under actual interest (target), and so simulation time will be dominated by updates of the crowders rather than the target.

In this thesis, based of an existing all-atom protein model with an empirical force field, we will construct a hybrid model where a target protein, Tryptophan-Cage, remain represented in fully atomistic detail, but a crowder protein, BPTI, will have a simplified representation. The side-chain groups that interact strongly with the target will keep their atomistic representation, keeping the existing parameterization of intermolecular interactions, but the rest of the atoms will be removed. The volume exclusion effect of the removed atoms will be restored by introducing a smooth repulsion potential defined as a spline function. Using relative entropy minimization, the parameters will be optimized to make the resulting coarse-grained model as similar as possible to the original, fully atomistic model.
We manage to replicate the main features of the energy landscape of the BPTI crowder, at least when interacting with Tryptophan-Cage, but further validation the correctness of the resulting model is needed. It is not clear yet that this coarse-graining approach can yield enough speedup, to motivate the usage of the new model. We would expect the speedup to be larger for bigger crowder molecules. (Less)
Please use this url to cite or link to this publication:
author
Linse, Björn LU
supervisor
organization
course
PHYM01 20151
year
type
H2 - Master's Degree (Two Years)
subject
keywords
Proteins, atomistic model, multi-scale modelling, Monte Carlo simulation, relative entropy
language
English
id
8500041
date added to LUP
2016-06-29 13:05:29
date last changed
2016-11-15 13:54:38
@misc{8500041,
  abstract     = {Of increasing interest in the field of protein modelling and simulation is the effects of crowding. In a living cell, large molecules can take up 30% of the cell plasma volume, and affects the folding and dynamics of proteins. Computer simulations have so far focused mainly on simple spherical crowders, but recent simulations with protein crowders have shown effects beyond what can be replicated using spherical crowders. However, this is a computational challenge as crowder proteins are much bigger than the protein under actual interest (target), and so simulation time will be dominated by updates of the crowders rather than the target.

In this thesis, based of an existing all-atom protein model with an empirical force field, we will construct a hybrid model where a target protein, Tryptophan-Cage, remain represented in fully atomistic detail, but a crowder protein, BPTI, will have a simplified representation. The side-chain groups that interact strongly with the target will keep their atomistic representation, keeping the existing parameterization of intermolecular interactions, but the rest of the atoms will be removed. The volume exclusion effect of the removed atoms will be restored by introducing a smooth repulsion potential defined as a spline function. Using relative entropy minimization, the parameters will be optimized to make the resulting coarse-grained model as similar as possible to the original, fully atomistic model.
We manage to replicate the main features of the energy landscape of the BPTI crowder, at least when interacting with Tryptophan-Cage, but further validation the correctness of the resulting model is needed. It is not clear yet that this coarse-graining approach can yield enough speedup, to motivate the usage of the new model. We would expect the speedup to be larger for bigger crowder molecules.},
  author       = {Linse, Björn},
  keyword      = {Proteins,atomistic model,multi-scale modelling,Monte Carlo simulation,relative entropy},
  language     = {eng},
  note         = {Student Paper},
  title        = {Simulation of proteins in crowded environments using coarse-graining methods},
  year         = {2016},
}