Lipid-mediated interactions tune the association of glycophorin A helix and its disruptive mutants in membranes

The specific and non-specific driving forces of helix association within membranes are still poorly understood. Here, we use coarse-grain molecular dynamics simulations to study the association behavior of glycophorin A and two disruptive mutants, T87F and a triple mutant of the GxxxG motif (G79LG83LG86L), embedded in a lipid membrane. Self-assembly simulations and the association free-energy profile confirm an energetically-favorable dimerized state for both the wild type and the mutants. The reduced association of the mutants compared to the wild type, as observed in experiments, can be justified from comparisons of the free energy profiles. Less-favorable protein-protein interactions as well as disruption of lipid packing around the mutant dimers is responsible for their reduced association. The role of the non-specific "lipid-phobic'' contribution appears to be as important as the specific "helix-helix'' contribution. However, the differences between the wild type and mutants are subtle and our simulations predict a dimerization state not only for the wild-type glycophorin A, but also for these 'disruptive' mutants. Our results highlight the importance of both specific as well as non-specific driving forces in the association of transmembrane helices, and point to the need of more careful interpretation of experimental measurements

Lipid-dependent conformational landscape of the ErbB2 growth factor receptor dimers

Altered lipid metabolism has been linked to cancer development and progression. Several roles have been attributed to the increased saturation and length of lipid acyl tails observed in tumors, but its effect on signaling receptors is still emerging. In this work, we have analyzed the lipid dependence of the ErbB2 growth factor receptor dimerization that plays an important role in the pathogenesis of breast cancer. We have performed coarse-grain ensemble molecular dynamics simulations to comprehensively sample the ErbB2 monomer-dimer association. Our results indicate a dynamic dimer state with a complex conformational landscape that is modulated with increasing lipid tail length. We resolve the native N-terminal "active" and C-terminal "inactive" conformations in all membrane compositions. However, the relative population of the N-terminal and C-terminal conformers is dependent on length of the saturated lipid tails. In short-tail membranes, additional non-specific dimers are observed which are reduced or absent in long-tailed bilayers. Our results indicate that the relative population as well as the structure of the dimer state is modulated by membrane composition. We have correlated these differences to local perturbations of the membrane around the receptor. Our work is an important step in characterizing ErbB dimers in healthy and diseased states and emphasize the importance of sampling lipid dynamics in understanding receptor association

Simulations of the c-subunit of ATP-synthase reveal helix rearrangements

The c-subunit of the enzyme, ATP synthase couples the proton movement through the a-subunit with its own rotation and subsequent rotation of the F1 ring to drive ATP synthesis. Here, we perform mu s time-scale coarse-grained molecular dynamics simulations of the c-subunit to characterize its structure and dynamics. Two different helix-helix inter-faces, albeit with similar interfacial characteristics, are sampled in the simulations. The helix-2 of the c-subunit monomer rotates around the axis of helix-1 bringing about a change in the interface. Previous models have also proposed such a change in the helix interface but postulated that helix-2 swivels around its own axis. Such large-scale changes in helix packing motifs have not been observed before. The helix-swirling persists even in the c-subunit ring but the dynamics is much slower. The cooperative behavior in the ring appears to stabilize a conformation less-populated in the monomer. Analyzing the stability of the c-subunit ring, it was found that: six lipid molecules arc necessary to fill the central cavity of the ring. These lipid molecules were not aligned with the surrounding bilayer but protruded towards the periplasmic side. The characterization of the monomer and ring presented in this work sheds light into the structural dynamics of the c-subunit and its functional relevance

Structural basis for the enhanced activity of cyclic antimicrobial peptides:The case of BPC194

AbstractWe report the molecular basis for the differences in activity of cyclic and linear antimicrobial peptides. We iteratively performed atomistic molecular dynamics simulations and biophysical measurements to probe the interaction of a cyclic antimicrobial peptide and its inactive linear analogue with model membranes. We establish that, relative to the linear peptide, the cyclic one binds stronger to negatively charged membranes. We show that only the cyclic peptide folds at the membrane interface and adopts a β-sheet structure characterised by two turns. Subsequently, the cyclic peptide penetrates deeper into the bilayer while the linear peptide remains essentially at the surface. Finally, based on our comparative study, we propose a model characterising the mode of action of cyclic antimicrobial peptides. The results provide a chemical rationale for enhanced activity in certain cyclic antimicrobial peptides and can be used as a guideline for design of novel antimicrobial peptides

Fluorescent Pigment and Phenol Glucosides from the Heartwood of Pterocarpus marsupium

The fluorescence shown by extracts of the heartwood of Pterocarpus marsupium is attributed to salts of the new compound 1, whose structure was elaborated using detailed spectroscopic/ spectrometric studies. The plant material also contains the nonfluorescent compounds 2 and 3. The absolute configuration of 1 was determined by experimental and theoretically calculated electronic CD spectra, while that of 3 was deduced from ECD comparison with reported results in the α-hydroxydihydrochalcone series

Understanding Conformational Dynamics of Complex Lipid Mixtures Relevant to Biology

This is a perspective article entitled “Frontiers in computational biophysics: understanding conformational dynamics of complex lipid mixtures relevant to biology” which is following a CECAM meeting with the same name.Fil: Friedman, Ran. Linnæus University; ArgentinaFil: Khalid, Syma. University of Southampton; Reino UnidoFil: Aponte Santamaría, Camilo. Ruprecht-Karls-Universität Heidelberg; Alemania. Universidad de los Andes; ColombiaFil: Arutyunova, Elena. University of Alberta; CanadáFil: Becker, Marlon. Westfälische Wilhelms Universität; AlemaniaFil: Boyd, Kevin J.. University of Connecticut; Estados UnidosFil: Christensen, Mikkel. University Aarhus; DinamarcaFil: Coimbra, João T. S.. Universidad de Porto; PortugalFil: Concilio, Simona. Universita di Salerno; ItaliaFil: Daday, Csaba. Heidelberg Institute for Theoretical Studies; AlemaniaFil: Eerden, Floris J. van. University of Groningen; Países BajosFil: Fernandes, Pedro A.. Universidad de Porto; PortugalFil: Gräter, Frauke. Heidelberg University; Alemania. Heidelberg Institute for Theoretical Studies; AlemaniaFil: Hakobyan, Davit. Westfälische Wilhelms Universität; AlemaniaFil: Heuer, Andreas. Westfälische Wilhelms Universität; AlemaniaFil: Karathanou, Konstantina. Freie Universität Berlin; AlemaniaFil: Keller, Fabian. Westfälische Wilhelms Universität; AlemaniaFil: Lemieux, M. Joanne. University of Alberta; CanadáFil: Marrink, Siewert J.. University of Groningen; Países BajosFil: May, Eric R.. University of Connecticut; Estados UnidosFil: Mazumdar, Antara. University of Groningen; Países BajosFil: Naftalin, Richard. Colegio Universitario de Londres; Reino UnidoFil: Pickholz, Mónica Andrea. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Física de Buenos Aires. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Física de Buenos Aires; ArgentinaFil: Piotto, Stefano. Universita di Salerno; ItaliaFil: Pohl, Peter. Johannes Kepler University; AustriaFil: Quinn, Peter. Colegio Universitario de Londres; Reino UnidoFil: Ramos, Maria J.. Universidad de Porto; PortugalFil: Schiøtt, Birgit. University Aarhus; DinamarcaFil: Sengupta, Durba. National Chemical Laboratory India; IndiaFil: Sessa, Lucia. Universita di Salerno; ItaliaFil: Vanni, Stefano. University Of Fribourg;Fil: Zeppelin, Talia. University Aarhus; DinamarcaFil: Zoni, Valeria. University of Fribourg; SuizaFil: Bondar, Ana-Nicoleta. Freie Universität Berlin; AlemaniaFil: Domene, Carmen. University of Oxford; Reino Unido. University of Bath; Reino Unid

Polarizable Water Model for the Coarse-Grained MARTINI Force Field

Coarse-grained (CG) simulations have become an essential tool to study a large variety of biomolecular processes, exploring temporal and spatial scales inaccessible to traditional models of atomistic resolution. One of the major simplifications of CG models is the representation of the solvent, which is either implicit or modeled explicitly as a van der Waals particle. The effect of polarization, and thus a proper screening of interactions depending on the local environment, is absent. Given the important role of water as a ubiquitous solvent in biological systems, its treatment is crucial to the properties derived from simulation studies. Here, we parameterize a polarizable coarse-grained water model to be used in combination with the CG MARTINI force field. Using a three-bead model to represent four water molecules, we show that the orientational polarizability of real water can be effectively accounted for. This has the consequence that the dielectric screening of bulk water is reproduced. At the same time, we parameterized our new water model such that bulk water density and oil/water partitioning data remain at the same level of accuracy as for the standard MARTINI force field. We apply the new model to two cases for which current CG force fields are inadequate. First, we address the transport of ions across a lipid membrane. The computed potential of mean force shows that the ions now naturally feel the change in dielectric medium when moving from the high dielectric aqueous phase toward the low dielectric membrane interior. In the second application we consider the electroporation process of both an oil slab and a lipid bilayer. The electrostatic field drives the formation of water filled pores in both cases, following a similar mechanism as seen with atomistically detailed models

Insights into the Energetics of Membrane-Bound Peptides : Towards an Understanding of the Structural Organisation of Membrane Proteins

A large number of key cellular functions such as signalling and transport are performed and regulated by membrane proteins. The focus of this thesis is on a sub-class of membrane proteins, namely the monotopic and bitopic peptides. Analysis of several aspects of these peptides such as their orientation, electrostatics and association is reported here. The environment of these peptides is represented by a continuum model that distinguishes between water, membrane core and head-group region. The orientation of membrane peptides such as glycophorin A and melittin is calculated and reproduces the experimentally-calculated tilt angles. The length dependence of synthetic peptides such as WALPs is reproduced and found to depend on the cost of cavity formation in the aqueous layer. It is shown that the solvent reaction field plays a crucial role in determining the orientation of polypeptides. The reaction field is also shown to screen the helix dipole of membrane-bound helices depending on the proximity and geometry of the aqueous phase relative to the helix termini. As a result, the helix dipole of transmembrane helices is found to decrease with peptide length. The analysis is extended to helices in soluble proteins and rules of thumb are established to estimate the effective helix dipole from visual inspection of protein structures. The association of glycophorin A helices is modelled and the decomposition of free energy of dimerisation shows a favourable contribution from the residues experimentally implicated to contribute to the process. The association of erythropoietin receptor transmembrane dimers and that of its mutants is also modelled. The inefficient lipid raft localisation of the T242N mutant is proposed to be related to its helix packing. The thesis provides insight into the structural organisation and energetics of membrane proteins