7 research outputs found
PARENT: A Parallel Software Suite for the Calculation of Configurational Entropy in Biomolecular Systems
Accurate estimation of configurational
entropy from the <i>in silico</i>-generated biomolecular
ensembles, e.g., from molecular
dynamics (MD) trajectories, is dependent strongly on exhaustive sampling
for physical reasons. This, however, creates a major computational
problem for the subsequent estimation of configurational entropy using
the Maximum Information Spanning Tree (MIST) or Mutual Information
Expansion (MIE) approaches for internal molecular coordinates. In
particular, the available software for such estimation exhibits serious
limitations when it comes to molecules with hundreds or thousands
of atoms, because of its reliance on a serial program architecture.
To overcome this problem, we have developed a parallel, hybrid MPI/openMP
C++ implementation of MIST and MIE, called PARENT, which is particularly
optimized for high-performance computing and provides efficient estimation
of configurational entropy in different biological processes (e.g.,
protein–protein interactions). In addition, PARENT also allows
for a detailed mapping of intramolecular allosteric networks. Here,
we benchmark the program on a set of 1-ÎĽs-long MD trajectories
of 10 different protein complexes and their components, demonstrating
robustness and good scalability. A direct comparison between MIST
and MIE on the same dataset demonstrates a superior convergence behavior
for the former approach, when it comes to total simulation length
and configurational-space binning
Self-Consistent Framework Connecting Experimental Proxies of Protein Dynamics with Configurational Entropy
The
recently developed NMR techniques enable estimation of protein
configurational entropy change from the change in the average methyl
order parameters. This experimental observable, however, does not
directly measure the contribution of intramolecular couplings, protein
main-chain motions, or angular dynamics. Here, we carry out a self-consistent
computational analysis of the impact of these missing contributions
on an extensive set of molecular dynamics simulations of different
proteins undergoing binding. Specifically, we compare the configurational
entropy change in protein complex formation as obtained by the maximum
information spanning tree approximation (MIST), which treats the above
entropy contributions directly, and the change in the average NMR
methyl and NH order parameters. Our parallel implementation of MIST
allows us to treat hard angular degrees of freedom as well as couplings
up to full pairwise order explicitly, while still involving a high
degree of sampling and tackling molecules of biologically relevant
sizes. First, we demonstrate a remarkably strong linear relationship
between the total configurational entropy change and the average change
in both methyl and backbone-NH order parameters. Second, in contrast
to canonical assumptions, we show that the main-chain and angular
terms contribute significantly to the overall configurational entropy
change and also scale linearly with it. Consequently, linear models
starting from the average methyl order parameters are able to capture
the contribution of main-chain and angular terms well. After applying
the quantum-mechanical harmonic oscillator entropy formalism, we establish
a similarly strong linear relationship for X-ray crystallographic
B-factors. Finally, we demonstrate that the observed linear relationships
remain robust against drastic undersampling and argue that they reflect
an intrinsic property of compact proteins. Despite their remarkable
strength, however, the above linear relationships yield estimates
of configurational entropy change whose accuracy appears to be sufficient
for qualitative applications only
Multistate Organization of Transmembrane Helical Protein Dimers Governed by the Host Membrane
Association of transmembrane (TM) helices taking place
in the cell
membrane has an important contribution to the biological function
of bitopic proteins, among which receptor tyrosine kinases represent
a typical example and a potent target for medical applications. Since
this process depends on a complex interplay of different factors (primary
structures of TM domains and juxtamembrane regions, composition and
phase of the local membrane environment, etc.), it is still far from
being fully understood. Here, we present a computational modeling
framework, which we have applied to systematically analyze dimerization
of 18 TM helical homo- and heterodimers of different bitopic proteins,
including the family of epidermal growth factor receptors (ErbBs).
For this purpose, we have developed a novel surface-based modeling
approach, which not only is able to predict particular conformations
of TM dimers in good agreement with experiment but also provides screening
of their conformational heterogeneity. Using all-atom molecular dynamics
simulations of several of the predicted dimers in different model
membranes, we have elucidated a putative role of the environment in
selection of particular conformations. Simulation results clearly
show that each particular bilayer preferentially stabilizes one of
possible dimer conformations, and that the energy gain depends on
the interplay between structural properties of the protein and the
membrane. Moreover, the character of protein-driven perturbations
of the bilayer is reflected in the contribution of a particular membrane
to the free energy gain. We have found that the approximated dimerization
strength for ErbBs family can be related to their oncogenic ability
Adaptable Lipid Matrix Promotes Protein–Protein Association in Membranes
The cell membrane is “stuffed”
with proteins, whose
transmembrane (TM) helical domains spontaneously associate to form
functionally active complexes. For a number of membrane receptors,
a modulation of TM domains’ oligomerization has been shown
to contribute to the development of severe pathological states, thus
calling for detailed studies of the atomistic aspects of the process.
Despite considerable progress achieved so far, several crucial questions
still remain: How do the helices recognize each other in the membrane?
What is the driving force of their association? Here, we assess the
dimerization free energy of TM helices along with a careful consideration
of the interplay between the structure and dynamics of protein and
lipids using atomistic molecular dynamics simulations in the hydrated
lipid bilayer for three different model systems – TM fragments
of glycophorin A, polyalanine and polyleucine peptides. We observe
that the membrane driven association of TM helices exhibits a prominent
entropic character, which depends on the peptide sequence. Thus, a
single TM peptide of a given composition induces strong and characteristic
perturbations in the hydrophobic core of the bilayer, which may facilitate
the initial “communication” between TM helices even
at the distances of 20–30 Å. Upon tight helix–helix
association, the immobilized lipids accommodate near the peripheral
surfaces of the dimer, thus disturbing the packing of the surrounding.
The dimerization free energy of the modeled peptides corresponds to
the strength of their interactions with lipids inside the membrane
being the lowest for glycophorin A and similarly higher for both homopolymers.
We propose that the ability to accommodate lipid tails determines
the dimerization strength of TM peptides and that the lipid matrix
directly governs their association
Role of Dimerization Efficiency of Transmembrane Domains in Activation of Fibroblast Growth Factor Receptor 3
Mutations
in transmembrane (TM) domains of receptor tyrosine kinases
are shown to cause a number of inherited diseases and cancer development.
Here, we use a combined molecular modeling approach to understand
molecular mechanism of effect of G380R and A391E mutations on dimerization
of TM domains of human fibroblast growth factor receptor 3 (FGFR3).
According to results of Monte Carlo conformational search in the implicit
membrane and further molecular dynamics simulations, TM dimer of this
receptor is able to form a number of various conformations, which
differ significantly by the free energy of association in a full-atom
model bilayer. The aforementioned mutations affect dimerization efficiency
of TM segments and lead to repopulation of conformational ensemble
for the dimer. Particularly, both mutations do not change the dimerization
free energy of the predominant (putative “non-active”)
symmetric conformation of TM dimer, while affect dimerization efficiency
of its asymmetric (“intermediate”) and alternative symmetric
(putative “active”) models. Results of our simulations
provide novel atomistic prospective of the role of G380 and A391E
mutations in dimerization of TM domains of FGFR3 and their consecutive
contributions to the activation pathway of the receptor
Antimicrobial Peptides Induce Growth of Phosphatidylglycerol Domains in a Model Bacterial Membrane
We performed microsecond long coarse-grained molecular dynamics simulations to elucidate the lateral structure and domain dynamics of a phosphatidylethanolamine (PE)/phosphatidylglycerol (PG) mixed bilayer (7/3), mimicking the inner membrane of gram-negative bacteria. Specifically, we address the effect of surface bound antimicrobial peptides (AMPs) on the lateral organization of the membrane. We find that, in the absence of the peptides, the minor PG fraction only forms small clusters, but that these clusters grow in size upon binding of the cationic AMPs. The presence of AMPs systematically affects the dynamics and induces long-range order in the structure of PG domains, stabilizing the separation between the two lipid fractions. Our results help in understanding the initial stages of destabilization of cytoplasmic bacterial membranes below the critical peptide concentration necessary for disruption, and provide a possible explanation for the multimodal character of AMP activity
The Conformation of the Epidermal Growth Factor Receptor Transmembrane Domain Dimer Dynamically Adapts to the Local Membrane Environment
The
epidermal growth factor receptor (EGFR) family is an important
class of receptor tyrosine kinases, mediating a variety of cellular
responses in normal biological processes and in pathological states
of multicellular organisms. Different modes of dimerization of the
human EGFR transmembrane domain (TMD) in different membrane mimetics
recently prompted us to propose a novel signal transduction mechanism
based on protein–lipid interaction. However, the experimental
evidence for it was originally
obtained with slightly different TMD fragments used in the two different
mimetics, compromising the validity of the comparison. To eliminate
ambiguity, we determined the nuclear magnetic resonance (NMR) structure
of the bicelle-incorporated dimer of the EGFR TMD fragment identical
to the one previously used in micelles. The NMR results augmented
by molecular dynamics simulations confirm the mutual influence of
the TMD and lipid environment, as is required for the proposed lipid-mediated
activation mechanism. They also reveal the possible functional relevance
of a subtle interplay between the concurrent processes in the lipid
and protein during signal transduction