Burstein, Shana R.

Erales, Jenny

Hess, Sara K.

Londergan, Casey H.

Longhi, Sonia

Wai, Rebecca B.

Elsevier - Publisher Connector 

Developing a Protocol for Ensemble and Vibrational Probe-Containing Molecular Dynamics Simulations of the Nipah Ntail-XD Complex 

Monday, February 9, 2015 227aIntrinsically Disordered Proteins (IDP) and
Aggregates II
1137-Pos Board B88
Optimized Force Fields for Simulations of Intrinsically Disordered
Proteins
Robert Best1, Wenwei Zheng1, Jeetain Mittal2.
1Laboratory of Chemical Physics, National Institutes of Health, Bethesda,
MD, USA, 2Department of Chemical Engineering, Lehigh University,
Bethlehem, PA, USA.
Some frequently encountered deficiencies in all-atom molecular simulations,
such as nonspecific protein-protein interactions being too strong, and unfolded
or disordered states being too collapsed, suggest that proteins are insufficiently
well solvated in simulations using current state-of-the-art force fields. In order to
address these issues, we make the simplest possible change, by modifying the
short-range protein-water pair interactions, and leaving all the water-water
and protein-protein parameters unchanged.We find that a modest strengthening
of protein-water interactions is sufficient to recover the correct dimensions of
intrinsically disorderedor unfoldedproteins, as determined bydirect comparison
with small-angleX-ray scattering (SAXS) and Fo¨rster resonance energy transfer
(FRET) data. The modification also results in more realistic protein:protein af-
finities, and average solvation free energies of model compounds which are
more consistent with experiment. Most importantly, we show that this scaling
is small enough not to affect adversely the stability of the folded state, with
only a modest effect on the stability of model peptides forming alpha-helix
and beta-sheet structures. The proposed adjustment opens the way to more accu-
rate atomistic simulations of proteins, particularly for intrinsically disordered
proteins, protein:protein association, and crowded cellular environments.
1138-Pos Board B89
Adaptive Particle Simulations of Alpha-Synuclein Fibril Formation
Ioana M. Ilie, Wouter K. den Otter, Wim J. Briels.
Computational Biophysics, University of Twente, Enschede, Netherlands.
A number of intrinsically disordered proteins, including alpha-synuclein and
beta-amyloid, are known to form amyloids in neurodegenerative diseases
such as Parkison’s and Alzheimer’s diseases, respectively, indicating generic
behaviour of this class of proteins. The accompanying large conformational
transition, from disordered to a beta-sheet, makes it difficult and extremely
time-consuming to study the aggregation process by standard simulation
methods. We have developed a Lambda Dynamics technique in which the
coarse-grained particles, representing sequences of consecutive amino acids,
respond to their environment by changing shape and interaction properties
[1]. The evolving states of the particles are determined by internal and external
interactions. The translational and rotational motion of the anisotropic particles
are simulated with a newly developed concise Brownian Dynamics algorithm
[2,3]. We present results on the aggregation of solvated spherical, disordered
proteins into fibrils of elongated, beta-sheet forming proteins.
[1] I.M. Ilie, W.K. den Otter and W.J. Briels, in preparation
[2] I.M. Ilie, W.J. Briels and W.K. den Otter, in preparation
[3] I.M. Ilie, W.K. den Otter and W.J. Briels, J. Chem. Phys. 141, 065101
(2014)
1139-Pos Board B90
What does Evolution Tell us about the Structure of a Functional Amyloid
Protein?
Pengfei Tian1, Wouter Boomsma2, Yong Wang2, Daniel Erik Otzen3,
Mogens Høgh Jensen1, Kresten Lindorff-Larsen2.
1Niels Bohr Institute, Copenhagen, Denmark, 2Department of Biology,
University of Copenhagen, Copenhagen, Denmark, 3Department of
Molecular Biology, Aarhus University, Copenhagen, Denmark.
Amyloids are insoluble fibrillar protein aggregates. While they are commonly
found in human diseases, it is becoming increasingly clear that this type of
structure is essential for a range of biological functions, with prominent exam-
ples in organisms ranging from bacteria to human. Functional amyloid and
pathogenic amyloid share similar physical and chemical properties. Unlike
pathological amyloids, however, the structures of functional amyloids are
formed by polypeptide sequences whose amyloid structure has been under a
positive evolutionary selection pressure. This important distinction provides
us with an opportunity to obtain structural insights from an unexpected source:
the covariation of amino acids among sequences within the same family of a
functional amyloid protein. There is a long history for the idea of using coevo-
lution for molecular structure prediction, but recent growth in sequence data-
bases and new, efficient algorithms to disentangle indirect couplings in a
network, have dramatically improved our ability to predict residue-residue con-
tacts. We used recently developed sequence analysis methods (EVcoupling,PSICOV and GREMLIN) to extract distance restraints from a multiple
sequence alignment of a functional amyloid protein. Together with an efficient
force field, these restraints allow us to determine atomic resolution structural
models. We find that the protein forms a beta-helical structure, where each
turn corresponds to previously identified repeat sequences. The proposed struc-
ture is validated by previously published solid-state NMR, electron microscopy
and X-ray diffraction data, and confirms an earlier proposed model derived by
complementary means. To our knowledge, this is the first time the analysis of
correlated mutations and computer simulations have been used together to
study the structure of a functional amyloid. The current study therefore serves
as a probe into the potential applicability of the approach in this domain.
1140-Pos Board B91
Enabling Biophysical Characterization of Intrinsically Disordered Protein
Ensembles
Chakra S. Chennubhotla1, Arvind Ramanathan2, Chris Stanley2.
1Computational Biology, University of Pittsburgh, Pittsburgh, PA, USA,
2Oak Ridge National Laboratory, Knoxville, TN, USA.
Elucidating structural details of protein conformations and its relation to protein
function is a forefront area in structural biology. In this project, we will investi-
gate nuclear co- activator binding domain (NCBD), an intrinsically disordered
protein (IDP) implicated in acute myeloid/lymphatic leukemia (AML/ALL),
which has the propensity to adopt extended conformations in unbound form
and undergoes synergistic folding with substrate specific conformations when
bound. Since IDPs like NCBD are highly flexible, their full conformational
range is not observable by any one structure determination technique. We
have developed a novel, integrated experimental and computational technique
to elicit high-resolution structural details of such IDP ensembles. Specifically,
we have (1) developed methods to prepare amino-acid-type selectively
deuterated NCBD and utilize SANS contrast variation techniques to refine
high-resolution conformational ensembles; (2) constructed parallel ensemble
simulation strategies on heterogeneous computer architectures to generatemilli-
second timescale atomistic simulations; and (3) designed Bayesian inference
techniques for statistical characterization of IDP conformational ensembles.
The integrated approach enables accurate understanding, simulation and predic-
tion of recognition mechanisms of NCBD under physiological condition.
1141-Pos Board B92
Developing a Protocol for Ensemble and Vibrational Probe-Containing
Molecular Dynamics Simulations of the Nipah Ntail-XD Complex
Shana R. Burstein1, Rebecca B. Wai1, Sara K. Hess1, Casey H. Londergan1,
Jenny Erales2, Sonia Longhi2.
1Chemistry, Haverford College, Haverford, PA, USA, 2CNRS-Marseille,
Marseille, France.
Intrinsically disordered proteins (IDPs) prove difficult to characterize using
typical protein secondary structure indicators, such as CD and NMR spectros-
copy, because of their dynamic nature. Molecular Dynamics (MD) simulations
can be adapted for use in highly dynamic systems such as IDPs through
enhanced sampling techniques. This project involves the characterization of
the ‘‘fuzzy’’ Nipah Virus nucleo- and phosphoprotein bound complex by using
MD simulations and vibrational probes. In order to run MD simulations on
IDPs, a viable structural ensemble must be generated; this can be done by vary-
ing the simulation temperature to overcome energy boundaries and exchanging
high-energy structures with those generated at low temperature (‘‘replica ex-
change’’). Once an ensemble of structures is generated, shorter simulations
can be run in which a site-specific thiocyanate probe is incorporated into
each structure. Eventually, an infrared (IR) lineshape can be simulated from
the conformational ensemble for each label site and directly compared to
experimental data. Progress towards each step of this multi-step simulation pro-
tocol will be discussed, as well as the prospects for a hybrid spectroscopic-
theoretical determination of the conformational distribution of ‘‘fuzzy’’ bound
complexes.
1142-Pos Board B93
Using Chemical Shifts to Generate Structural Ensembles for Intrinsically
Disordered Proteins with Converged Distributions of Secondary Structure
F. Marty Ytreberg1, Wade Borcherds2, HongweiWu3, GaryW. Daughdrill2.
1University of Idaho, Moscow, ID, USA, 2University of South Florida,
Tampa, FL, USA, 3Indiana University, Bloomington, IN, USA.
A short segment of the disordered p53 transactivation domain (p53TAD) forms
an amphipathic helix when bound to the E3 ubiquitin ligase, MDM2. In the un-
bound p53TAD, this short segment has transient helical secondary structure.
Using a method that combines broad sampling of conformational space with
re-weighting, it is shown that it is possible to generate multiple, independent
structural ensembles that have highly similar secondary structure distributions
for both p53TAD and a P27A mutant. Fractional amounts of transient helical


Archive Ouverte en Sciences de l'Information et de la Communication

Developing a Protocol for Ensemble and Vibrational Probe-Containing Molecular Dynamics Simulations of the Nipah Ntail-XD Complex

Shana R. Burstein

Rebecca B. Wai

Sara K. Hess

Casey H. Londergan

Jenny Erales

Sonia Longhi

Crossref

Biophysical Journal

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Developing a Protocol for Ensemble and Vibrational Probe-Containing Molecular Dynamics Simulations of the Nipah Ntail-XD Complex

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