03212nas a2200217   4500008004100000022001400041245010100055210006900156260007100225300001400296490000700310520238000317100002602697700002502723700002802748700002002776700002502796700002002821700002602841856012702867       2015                        eng d  a1549-961800aHigh-throughput simulations of dimer and trimer assembly of membrane proteins. the DAFT approach0 aHighthroughput simulations of dimer and trimer assembly of membr  a1155 16TH ST, NW, WASHINGTON, DC 20036 USAbAMER CHEMICAL SOCcMAY  a2278-22910 v113 a<p>Interactions between membrane proteins are of great biological significance and are consequently an important target for pharmacological intervention. Unfortunately, it is still difficult to obtain detailed views on such interactions, both experimentally, where the environment hampers atomic resolution investigation, and computationally, where the time and length scales are problematic. Coarse grain simulations have alleviated the later issue, but the slow movement through the bilayer, coupled to the long life times of nonoptimal dimers, still stands in the way of characterizing binding distributions. In this work, we present DAFT, a Docking Assay For Transmembrane components, developed to identify preferred binding orientations. The method builds on a program developed recently for generating custom membranes, called insane (INSert membrANE). The key feature of DAFT is the setup of starting structures, for which optimal periodic boundary conditions are devised. The purpose of DAFT is to perform a large number of simulations with different components, starting from unbiased noninteracting initial states, such that the simulations evolve collectively, in a manner reflecting the underlying energy landscape of interaction. The implementation and characteristic features of DAFT are explained, and the efficacy and relaxation properties of the method are explored for oligomerization of glycophorin A dimers, polyleucine dimers and trimers, MS1 trimers, and rhodopsin dimers. The results suggest that, for simple helices, such as GpA and polyleucine, in POPC/DOPC membranes series of 500 simulations of 500 ns each allow characterization of the helix dimer orientations and allow comparing associating and nonassociating components. However, the results also demonstrate that short simulations may suffer significantly from nonconvergence of the ensemble and that using too few simulations may obscure or distort features of the interaction distribution. For trimers, simulation times exceeding several microseconds appear needed, due to the increased complexity. Similarly, characterization of larger proteins, such as rhodopsin, takes longer time scales due to the slower diffusion and the increased complexity of binding interfaces. DAFT and its auxiliary programs have been made available from http://cgmartini.nl/, together with a working example.</p>1 aWassenaar, Tsjerk, A.1 aPluhackova, Kristyna1 aMoussatova, Anastassiia1 aSengupta, Durba1 aMarrink, Siewert-Jan1 aTieleman, Peter1 aBoeckmann, Rainer, A.  uhttps://library.ncl.res.in/content/high-throughput-simulations-dimer-and-trimer-assembly-membrane-proteins-daft-approach-000834nas a2200205   4500008004100000022001400041245010800055210006900163260008000232300001400312490000800326100002600334700002500360700002800385700002000413700002500433700002000458700002600478856012400504       2015                        eng d  a0006-349500aLandscapes of membrane protein interactions from high-throughput MD simulations using the daft approach0 aLandscapes of membrane protein interactions from highthroughput   a600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USAbBiophys SoccJAN  a526A-526A0 v1081 aWassenaar, Tsjerk, A.1 aPluhackova, Kristyna1 aMoussatova, Anastassiia1 aSengupta, Durba1 aMarrink, Siewert-Jan1 aTieleman, Peter1 aBoeckmann, Rainer, A.  uhttps://library.ncl.res.in/content/landscapes-membrane-protein-interactions-high-throughput-md-simulations-using-daft-002001nas a2200205   4500008004100000022001400041245008200055210006900137260011000206300001400316490000700330520119600337100002401533700002501557700002501582700002601607700002601633700002001659856011601679       2015                        eng d  a1463-907600aThermodynamic and kinetic characterization of transmembrane helix association0 aThermodynamic and kinetic characterization of transmembrane heli  aTHOMAS GRAHAM HOUSE, SCIENCE PARK, MILTON RD, CAMBRIDGE CB4 0WF, CAMBS, ENGLANDbROYAL SOC CHEMISTRYcNOV  a1390-13980 v173 a<p>The transient dimerization of transmembrane proteins is an important event in several cellular processes and computational methods are being increasingly used to quantify their underlying energetics. Here, we probe the thermodynamics and kinetics of a simple transmembrane dimer to understand membrane protein association. A multi-step framework has been developed in which the dimerization profiles are calculated from coarse-grain molecular dynamics simulations, followed by meso-scale simulations using parameters calculated from the coarse-grain model. The calculated value of Delta G(assoc) is approx. -20 kJ mol(-1) and is consistent between three methods. Interestingly, the meso-scale stochastic model reveals low dimer percentages at physiologically-relevant concentrations, despite a favorable Delta G(assoc). We identify generic driving forces arising from the protein backbone and lipid bilayer and complementary factors, such as protein density, that govern self-interactions in membranes. Our results provide an important contribution in understanding membrane protein organization and linking molecular, nano-scale computational studies to meso-scale experimental data.</p>1 aPawar, Aiswarya, B.1 aDeshpande, Sneha, A.1 aGopal, Srinivasa, M.1 aWassenaar, Tsjerk, A.1 aAthale, Chaitanya, A.1 aSengupta, Durba  uhttps://library.ncl.res.in/content/thermodynamic-and-kinetic-characterization-transmembrane-helix-association-002311nas a2200241   4500008004100000022001400041245008800055210006900143260000800212300001100220490000800231520148500239653001601724653001801740653003901758653003101797653003001828100002501858700002401883700002601907700002001933856011601953       2020                        eng d  a0009-308400aLipid-dependent conformational landscape of the ErbB2 growth factor receptor dimers0 aLipiddependent conformational landscape of the ErbB2 growth fact  cAUG  a1049110 v2303 a<p>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.</p>
10aErbB2 dimer10aLipid effects10aMartini coarse-grained simulations10aMembrane protein structure10aTransmembrane association1 aGopal, Srinivasa, M.1 aPawar, Aiswarya, B.1 aWassenaar, Tsjerk, A.1 aSengupta, Durba  uhttps://library.ncl.res.in/content/lipid-dependent-conformational-landscape-erbb2-growth-factor-receptor-dimers