Thermal Stability of Apolipoprotein A-I in High-Density Lipoproteins by Molecular Dynamics

Jones, Martin K.; Catte, Andrea; Patterson, James C.; Gu, Feifei; Chen, Jianguo; L, Li; Segrest, Jere P.

doi:10.1016/j.bpj.2008.09.041

Cited by 33 publications

(68 citation statements)

References 58 publications

(90 reference statements)

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“…With the exception of R188, all other fi ve residues involved in salt bridges are conserved in mammals. Consistently with these observations, temperature jump molecular dynamic simulation ( 30,31 ) indicated that the E89-R177 and E111-H155 are more stable than the E78-R188 salt bridge. Thus it is possible that elimination of the negatively charged residues D89 and E111 and, to a lesser extent, E78, may destabilize the intermolecular interactions of the apoA-I dimer or the hairpin bound to HDL and may predispose to dyslipidemia.…”

Section: Binding Of Apoa-i Forms To Triglyceride-rich Emulsionssupporting

confidence: 60%

Alteration of negatively charged residues in the 89 to 99 domain of apoA-I affects lipid homeostasis and maturation of HDL

Kateifides

Gorshkova

Duka

et al. 2011

Journal of Lipid Research

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Section: Binding Of Apoa-i Forms To Triglyceride-rich Emulsionssupporting

confidence: 60%

Alteration of negatively charged residues in the 89 to 99 domain of apoA-I affects lipid homeostasis and maturation of HDL

Kateifides

Gorshkova

Duka

et al. 2011

Journal of Lipid Research

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“…A second weakness in the SANS data is that the ratio of 200 POPC to 2 apoA-I used does not form stable dimeric (R2) apoA-I particles (12,40). Because SANS data collection takes many hours, particle fusion may have occurred during this long time in the neutron beam, thus confusing the curve fitting.…”

Section: Discussionmentioning

confidence: 99%

Assessment of the Validity of the Double Superhelix Model for Reconstituted High Density Lipoproteins

Jones

Zhang

Catte

et al. 2010

Journal of Biological Chemistry

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High density lipoproteins (HDL) represent a heterogeneous population of particles with apoA-I as the major protein (1). Whether apoA-I/HDL 2 plays a direct role in cardiovascular disease prevention (e.g. removal of cholesterol from clogged arteries) or an indirect one (e.g. acts as a platform for the clustering of protective molecules, such as anti-inflammatory or antioxidant proteins), detailed knowledge of HDL structure is a key to understanding the molecular mechanism underlying these processes. Because the conformation of apoA-I on HDL is highly plastic (1), understanding apoA-I/HDL structure and dynamics is not straightforward.Since the early 1970s, the standard model for HDL particles reconstituted from apolipoprotein A-I (apoA-I) and phospholipid (apoA-I/HDL) has been that of a discoidal particle on the order of 100 Å in diameter and the thickness of a phospholipid bilayer. The initial observation of discoidal HDL particles was made by Forte et al. (2) when they examined HDL from patients with familial lecithin:cholesterol acyltransferase deficiency by negative stain EM. Reconstituted apoA-I/HDL particles (3) and nascent HDL from lymph (4) were then observed by negative stain EM to also have a discoidal shape. X-ray and neutron scattering studies (5, 6) provided further support for the standard discoidal model. The standard discoidal model has been used to interpret the results of a large number of experimental studies of the structure of reconstituted apoA-I/HDL particles. For review, see however, Wu et al. (11) used small angle neutron scattering to develop a model for apoA-I/HDL particles that is dramatically different from the standard model. In their model, termed a double superhelix (DSH), apoA-I possesses an open helical shape that twists around a central prolate ellipsoidal particle resembling a partial type I hexagonal lyotropic liquid crystalline phase.The DSH model is interesting. It is similar to MD simulation-based models (12) in that the proposed double superhelix forms a left-handed spiral as it wraps around the prolate ellip-

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“…Further details about CG parameters can also be found in our previous work ( 18 ). The protein secondary structure was assigned using as a reference the one generated by AA simulations ( 13 ). This approach was employed to give more fl exibility to the apoA-I chains ( 12,18 ) of the previously described CG simulations for particles of identical molar ratios.…”

Section: Cg Force Fi Eldmentioning

confidence: 99%

“…Cross-linking data by Silva et al ( 34 ) suggests the simulations of dHDL and sHDL ( 12 ). More recently, we developed methodology termed particle shrinkage that allows simulation of dHDL containing full-length apoA-I (12)(13)(14)(15).…”

Section: Cg MD Simulationsmentioning

confidence: 99%

MD simulations suggest important surface differences between reconstituted and circulating spherical HDL

Segrest

Jones

Catte

2013

Journal of Lipid Research

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The common lipid-associating motif in apoA-I is the amphipathic ␣ helix ( 2, 3 ). The fi rst tangible experimental evidence for the conformation of apoA-I on the edge of discoidal HDL (dHDL) was determination of a 4 Å resolution solution phase X-ray structure for residues 44-243 of lipid-free apoA-I reported by Borhani et al. in 1997 ( 4 ) that suggested an antiparallel double-belt model. In the fi rst experimental test of the belt model, Axelsen et al. ( 5 ) used polarized attenuated total internal refl ection Fourier-transform infrared spectroscopy to conclude that the result unambiguously supported a belt model. Theoretical considerations of the geometric and physical chemical nature of the apoA-I double-belt model resulted in the publication by our lab of an atomic resolution, antiparallel, double-belt, amphipathic helical model for dHDL ( 6 ) with a helix-helix registry termed LL5/5 oriented by salt bridges ( 6 ) surrounding the edge of a bilayer disc. Five laboratories subsequently have studied reconstituted dHDL using a variety of physical chemical methods, and the results have been consistent with our double-belt model ( 7-11 ). This model provided sound theoretical rationale for use of the lipid-free X-ray crystal structure as a valid model for molecular dynamics (MD) simulations of lipid-associated apoA-I. Comparison of the results of our MD simulations of the antiparallel, full-length apoA-I structure from an ensemble of 16 MD simulations of 105 Å dHDL ( 12-15 ) with the highresolution C-truncated crystal structure of apoA-I by Mei and Atkinson ( 16 ) validates many of our key published MD fi ndings ( 17 ).We previously published MD simulations of sHDL using N-terminally truncated ( ⌬ 43)apoA-I ( 18 ). We also investigated the dynamics of the activation of LCAT by apoA-I using both all-atom (AA) and coarse-grained (CG) MD Abstract Since spheroidal HDL particles (sHDL) are highly dynamic, molecular dynamics (MD) simulations are useful for obtaining structural models. Here we use MD to simulate sHDL with stoichiometries of reconstituted and circulating particles. The hydrophobic effect during simulations rapidly remodels discoidal HDL containing mixed lipids to sHDL containing a cholesteryl ester/triglyceride (CE/TG) core. We compare the results of simulations of previously characterized reconstituted sHDL particles containing two or three apoA-I created in the absence of phospholipid transfer protein (PLTP) with simulations of circu lating human HDL containing two or three apoA-I without apoA-II. We fi nd that circulating sHDL compared with reconstituted sHDL with the same number of apoA-I per particle contain approximately equal volumes of core lipid but signifi cantly less surface lipid monolayers. We conclude that in vitro reconstituted sHDL particles contain kinetically trapped excess phospholipid and are less than ideal models for circulating sHDL particles. In the circulation, phospholipid transfer via PLTP decreases the ratio of phospholipid to apolipoprotein for all sHDL particles. Further, sH...

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Thermal Stability of Apolipoprotein A-I in High-Density Lipoproteins by Molecular Dynamics

Cited by 33 publications

References 58 publications

Alteration of negatively charged residues in the 89 to 99 domain of apoA-I affects lipid homeostasis and maturation of HDL

Alteration of negatively charged residues in the 89 to 99 domain of apoA-I affects lipid homeostasis and maturation of HDL

Assessment of the Validity of the Double Superhelix Model for Reconstituted High Density Lipoproteins

MD simulations suggest important surface differences between reconstituted and circulating spherical HDL

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