4 research outputs found
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
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
Impact of membrane partitioning on the spatial structure of an S-type cobra cytotoxin
<p>Cobra cytotoxins (CTs) belong to the three-fingered protein family. They are classified into S- and P-types, the latter exhibiting higher membrane-perturbing capacity. In this work, we investigated the interaction of CTs with phospholipid bilayers, using coarse-grained (CG) and full-atom (FA) molecular dynamics (MD). The object of this work is a CT of an S-type, cytotoxin I (CT1) from <i>N.oxiana</i> venom. Its spatial structure in aqueous solution and in the micelles of dodecylphosphocholine (DPC) were determined by <sup>1</sup>H-NMR spectroscopy. Then, via CG- and FA MD-computations, we evaluated partitioning of CT1 molecule into palmitoyloleoylphosphatidylcholine (POPC) membrane, using the toxin spatial models, obtained either in aqueous solution, or detergent micelle. The latter model exhibits minimal structural changes upon partitioning into the membrane, while the former deviates from the starting conformation, loosing the tightly bound water molecule in the loop-2. These data show that the structural changes elicited by CT1 molecule upon incorporation into DPC micelle take place likely in the lipid membrane, although the mode of the interaction of this toxin with DPC micelle (with the tips of the all three loops) is different from its mode in POPC membrane (primarily with the tip of the loop-1 and both the tips of the loop-1 and loop-2).</p
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