THESIS
2013
xvi, 151 pages : illustrations ; 30 cm
Abstract
This thesis mainly focuses on modeling protein conformational dynamics using kinetic network
models. Protein conformational dynamics are crucial for a wide range of biological processes
including protein folding and the operation of key cellular machinery. Kinetic network models,
especially Markov State Models (MSMs), have become a popular approach for investigating the
conformational dynamics of proteins and other biomolecules. MSMs are typically built from
numerous molecular dynamics simulations by dividing the sampled configurations into a large
number of microstates based on geometric criteria. The resulting microstate model can then be
coarse-grained into a more understandable macrostate model by lumping together rapidly mixing
microstates into larger, metastable aggregates...[
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This thesis mainly focuses on modeling protein conformational dynamics using kinetic network
models. Protein conformational dynamics are crucial for a wide range of biological processes
including protein folding and the operation of key cellular machinery. Kinetic network models,
especially Markov State Models (MSMs), have become a popular approach for investigating the
conformational dynamics of proteins and other biomolecules. MSMs are typically built from
numerous molecular dynamics simulations by dividing the sampled configurations into a large
number of microstates based on geometric criteria. The resulting microstate model can then be
coarse-grained into a more understandable macrostate model by lumping together rapidly mixing
microstates into larger, metastable aggregates.
However, finite sampling often results in the creation of many poorly sampled microstates. We
propose formalism based on an algebraic principle for matrix approximation, i.e., the Nyström
method, to deal with such poorly sampled microstates. Our scheme builds a hierarchy of
microstates from high to low populations and progressively applies spectral clustering on sets of
microstates within each level of the hierarchy. It helps spectral clustering identify metastable
aggregates with highly populated microstates rather than being distracted by lowly populated
states. We demonstrate the ability of this algorithm to discover the major metastable states on
several protein systems: the alanine dipeptide, trpzip2 peptide and sugar-free D-glucose/D-galactose
binding protein (apo GGBP).
Particularly for trpzip2 system, a computational protocol of simulating the T-jump peptide
unfolding experiments and the related transient IR and two-dimensional IR (2DIR) spectra based
on the Markov state model (MSM) and nonlinear exciton propagation (NEP) methods are proposed. We show that results from MSMs constructed from a large number of simulations
have a much better agreement with the equilibrium experimental 2DIR spectra compared to that
generated from straightforward MD simulations starting from the folded state. The agreement of
the simulation using MSMs and NEP with the experiment not only provides a justification for
our protocol, but also provides the physical insight of the underlying spectroscopic observables.
Besides FTIR and 2DIR, vibrationally resolved fluorescence spectra of the β-hairpin trpzip2
peptide at two temperatures as well as during a T-jump unfolding process are also simulated on
the basis of a combination of Markov state models and quantum chemistry schemes in this thesis.
Through further theoretical study, it is found that both the environment's electric field and the
chromophores’ geometry distortions are responsible for tryptophan.
The conformational dynamics of apo GGBP is a vital part of the entire binding process,
understanding of which is important for the design of inhibitors or mutations of the protein.
Markov State Models (MSMs) constructed from many all-atom molecular dynamics simulations
in the explicit solvent have identified multiple meta-stable conformational states of the apo
GGBP. These results suggest that domain-domain repulsive interactions play a crucial role in the
conformational dynamics of apo GGBP. Moreover, the metastable states mapped out by our
MSM for apo GGBP agrees well with previous simulation work, and the rapid equilibrium has
also been observed in NMR experiment. The result suggests the existing crystal structures may
not represent the dominant conformations in solution.
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