scholarly journals Evolutionary and Structural Constraints Influencing Apolipoprotein A-I Amyloid Behavior

2020 ◽  
Author(s):  
RA Gisonno ◽  
T Masson ◽  
N Ramella ◽  
EE Barrera ◽  
V Romanowski ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Md Simulations ◽  
Full Length ◽  
Saturation Mutagenesis ◽  
List Type ◽  
Structural Constraints ◽  
Helix Bundle ◽  
Apolipoprotein A ◽  
Partial Unfolding ◽  
Α Helix

AbstractApolipoprotein A-I (apoA-I) has a key function in the reverse cholesterol transport mediated by the high-density lipoprotein (HDL) particles. However, aggregation of apoA-I single point mutants can lead to hereditary amyloid pathology. Although several studies have tackled the biophysical and structural impacts introduced by these mutations, there is little information addressing the relationship between the evolutionary and structural features that contribute to the amyloid behavior of apoA-I. We combined evolutionary studies, in silico saturation mutagenesis and molecular dynamics (MD) simulations to provide a comprehensive analysis of the conservation and pathogenic role of the aggregation-prone regions (APRs) present in apoA-I. Sequence analysis demonstrated the pervasive conservation of an APR, designated here APR1, within the N-terminal α-helix bundle. Moreover, stability analysis carried out with the FoldX engine showed that this motif contributes to the marginal stability of apoA-I. Structural properties of the full-length apoA-I model suggest that aggregation is avoided by placing APRs into highly packed and rigid portions of its structure. Compared to HDL-deficiency or natural silent variants extracted from the gnomAD database, the thermodynamic and pathogenic impact of apoA-I point mutations associated with amyloid pathologies were found to show a higher destabilizing effect. MD simulations of the amyloid variant G26R evidenced the partial unfolding of the α-helix bundle and the occurrence of β-strand secondary elements at the C-terminus of apoA-I. Our findings highlight APR1 as a relevant component for apoA-I structural integrity and emphasize a destabilizing effect of amyloid variants that leads to the exposure of APRs. This information contributes to our understanding of how apoA-I, with its high degree of structural flexibility, maintains a delicate equilibrium between its native structure and intrinsic tendency to form amyloid aggregates. In addition, our stability measurements could be used as a proxy to interpret the structural impact of new mutations affecting apoA-I.HighlightsAggregation-prone region 1 (APR1), comprising residues 14-19, is consistently conserved during the evolutionary history of Apolipoprotein A-I.APR1 contributes to thermal stability of the α-helix bundle in the full-length Apolipoprotein A-I model.Amyloid variants introduce a destabilizing effect on the monomer structure of Apolipoprotein A-I, in contrast to HDL-deficiency and naturally-occurring variants, which are nearly neutral.During molecular dynamics simulations, G26R amyloidogenic mutant lead to the partial unfolding of α-helix bundle and exposure of APR1.

Amphipathic α-Helix Bundle Organization of Lipid-Free Chicken Apolipoprotein A-I†

Biochemistry ◽  
1999 ◽  
Vol 38 (14) ◽  
pp. 4327-4334 ◽  
Author(s):  
Robert S. Kiss ◽  
Cyril M. Kay ◽  
Robert O. Ryan
Keyword(s):  
Helix Bundle ◽  
Apolipoprotein A ◽  
Α Helix

scholarly journals The C-Terminus of Perilipin 3 Shows Distinct Lipid Binding at Phospholipid-Oil-Aqueous Interfaces

Membranes ◽  
2021 ◽  
Vol 11 (4) ◽  
pp. 265
Author(s):  
Amber R. Titus ◽  
Ellyse N. Ridgway ◽  
Rebecca Douglas ◽  
Elena Sánchez Brenes ◽  
Elizabeth K. Mann ◽  
...  
Keyword(s):  
Lipid Bilayers ◽  
Binding Proteins ◽  
Lipid Binding ◽  
Full Length ◽  
Lipid Monolayer ◽  
Lipid Monolayers ◽  
Aqueous Interfaces ◽  
Helix Bundle ◽  
C Terminus ◽  
Α Helix

Lipid droplets (LDs) are ubiquitously expressed organelles; the only intracellular organelles that contain a lipid monolayer rather than a bilayer. Proteins localize and bind to this monolayer as they do to intracellular lipid bilayers. The mechanism by which cytosolic LD binding proteins recognize, and bind, to this lipid interface remains poorly understood. Amphipathic α-helix bundles form a common motif that is shared between cytosolic LD binding proteins (e.g., perilipins 2, 3, and 5) and apolipoproteins, such as apoE and apoLp-III, found on lipoprotein particles. Here, we use pendant drop tensiometry to expand our previous work on the C-terminal α-helix bundle of perilipin 3 and the full-length protein. We measure the recruitment and insertion of perilipin 3 at mixed lipid monolayers at an aqueous-phospholipid-oil interface. We find that, compared to its C-terminus alone, the full-length perilipin 3 has a higher affinity for both a neat oil/aqueous interface and a phosphatidylcholine (PC) coated oil/aqueous interface. Both the full-length protein and the C-terminus show significantly more insertion into a fully unsaturated PC monolayer, contrary to our previous results at the air-aqueous interface. Additionally, the C-terminus shows a preference for lipid monolayers containing phosphatidylethanolamine (PE), whereas the full-length protein does not. These results strongly support a model whereby both the N-terminal 11-mer repeat region and C-terminal amphipathic α-helix bundle domains of perilipin 3 have distinct lipid binding, and potentially biological roles.

MOLECULAR DYNAMICS SIMULATIONS OF HELIX BUNDLE PROTEINS USING UNRES FORCE FIELD AND ALL-ATOM FORCE FIELD

2012 ◽  
Vol 11 (06) ◽  
pp. 1201-1215 ◽  
Author(s):  
KAIFU GAO ◽  
MINGHUI YANG
Keyword(s):  
Molecular Dynamics ◽  
Force Field ◽  
Protein A ◽  
Md Simulations ◽  
Time Frame ◽  
Coarse Grained ◽  
Staphylococcal Protein A ◽  
Villin Headpiece ◽  
Helix Bundle ◽  
Dynamics Simulations

We have investigated the folding of two helix-bundle proteins, 36-residue Villin headpiece and 56-residue E-domain of Staphylococcal protein A, by combining molecular dynamics (MD) simulations with Coarse-Grained United-Residue (UNRES) Force Field and all-atom force field. Starting from extended structures, each of the proteins was folded to a stable structure within a short time frame using the UNRES model. However, the secondary structures of helices were not well formed. Further refinement using MD simulations with the all-atom force field was able to fold the protein structure into the native-like state with the smallest main-chain root-mean-square deviation of around 3 Å. Detailed analysis of the folding trajectories was presented and the performance of GPU-based MD simulations was also discussed.

scholarly journals Nanostructure and stability of calcitonin amyloids

2017 ◽  
Vol 292 (18) ◽  
pp. 7348-7357 ◽  
Author(s):  
Federica Rigoldi ◽  
Pierangelo Metrangolo ◽  
Alberto Redaelli ◽  
Alfonso Gautieri
Keyword(s):  
Amyloid Fibrils ◽  
Md Simulations ◽  
Full Length ◽  
Structural Basis ◽  
Human Calcitonin ◽  
Nmr Data ◽  
Parallel Arrangement ◽  
Β Sheets ◽  
Α Helix ◽  
Β Sheet

Calcitonin is a 32-amino acid thyroid hormone that can form amyloid fibrils. The structural basis of the fibril formation and stabilization is still debated and poorly understood. The reason is that NMR data strongly suggest antiparallel β-sheet calcitonin assembly, whereas modeling studies on the short DFNKF peptide (corresponding to the sequence from Asp15 to Phe19 of human calcitonin and reported as the minimal amyloidogenic module) show that it assembles with parallel β-sheets. In this work, we first predict the structure of human calcitonin through two complementary molecular dynamics (MD) methods, finding that human calcitonin forms an α-helix. We use extensive MD simulations to compare previously proposed calcitonin fibril structures. We find that two conformations, the parallel arrangement and one of the possible antiparallel structures (with Asp15 and Phe19 aligned), are highly stable and ordered. Nonetheless, fibrils with parallel molecules show bulky loops formed by residues 1 to 7 located on the same side, which could limit or prevent the formation of larger amyloids. We investigate fibrils formed by the DFNKF peptide by simulating different arrangements of this amyloidogenic core sequence. We show that DFNKF fibrils are highly stable when assembled in parallel β-sheets, whereas they quickly unfold in antiparallel conformation. Our results indicate that the DFNKF peptide represents only partially the full-length calcitonin behavior. Contrary to the full-length polypeptide, in fact, the DFNKF sequence is not stable in antiparallel conformation, suggesting that the residue flanking the amyloidogenic peptide contributes to the stabilization of the experimentally observed antiparallel β-sheet packing.

scholarly journals Prediction of hyaluronic acid target on sucrase-isomaltase (SI) with reverse docking and molecular dynamics simulations for inhibitors binding to SI

PLoS ONE ◽  
2021 ◽  
Vol 16 (7) ◽  
pp. e0255351
Author(s):  
Xiao Li ◽  
Keqing Qian ◽  
Weiwei Han
Keyword(s):  
Molecular Dynamics ◽  
Biological Activities ◽  
Md Simulations ◽  
Inhibitor Binding ◽  
Medicinal Value ◽  
Human Immune ◽  
Hyaluronic Acids ◽  
Α Helix ◽  
Dynamics Simulations ◽  
White Mutant

Auricularia cornea (E.) polysaccharide is an important component of A. cornea Ehrenb, a white mutant strain of Auricularia with biological activities, such as enhancement of human immune function and cancer prevention. The hyaluronic acids (HAs) are important components of the A. cornea polysaccharide and have extremely high medicinal value. In this study, we used HA to search the target protein sucrase-isomaltase (SI). In addition, we also performed molecular dynamics (MD) simulations to explore the binding of three inhibitors (HA, acarbose and kotalanol) to SI. The MD simulations indicated that the binding of the three inhibitors may induce the partial disappearance of α helix in residues 530–580. Hence, the hydrogen bond for Gly570-Asn572, which was near the catalytic base Asp471 in SI, was broken during the binding of the three inhibitors. We reveal a new inhibitor for SI and provide reasonable theoretical clues for inhibitor binding to SI.

scholarly journals Molecular Architecture of Full-Length KcsA

2001 ◽  
Vol 117 (2) ◽  
pp. 165-180 ◽  
Author(s):  
D. Marien Cortes ◽  
Luis G. Cuello ◽  
Eduardo Perozo
Keyword(s):  
Three Dimensional ◽  
Full Length ◽  
Spin Interaction ◽  
Structural Constraints ◽  
Molecular Architecture ◽  
Paramagnetic Resonance ◽  
Gating Mechanism ◽  
Potassium Channel Kcsa ◽  
Site Directed Spin Labeling ◽  
Α Helix

The molecular architecture of the NH2 and COOH termini of the prokaryotic potassium channel KcsA has been determined using site-directed spin-labeling methods and paramagnetic resonance EPR spectroscopy. Cysteine mutants were generated (residues 5–24 and 121–160) and spin labeled, and the X-band CW EPR spectra were obtained from liposome-reconstituted channels at room temperature. Data on probe mobility (ΔHo−1), accessibility parameters (ΠO2 and ΠNiEdda), and inter-subunit spin-spin interaction (Ω) were used as structural constraints to build a three-dimensional folding model of these cytoplasmic domains from a set of simulated annealing and restrained molecular dynamics runs. 32 backbone structures were generated and averaged using fourfold symmetry, and a final mean structure was obtained from the eight lowest energy runs. Based on the present data, together with information from the KcsA crystal structure, a model for the three-dimensional fold of full-length KcsA was constructed. In this model, the NH2 terminus of KcsA forms an α-helix anchored at the membrane–water interface, while the COOH terminus forms a right-handed four-helix bundle that extend some 40–50 Å towards the cytoplasm. Functional analysis of COOH-terminal deletion constructs suggest that, while the COOH terminus does not play a substantial role in determining ion permeation properties, it exerts a modulatory role in the pH-dependent gating mechanism.

scholarly journals Amino Acid Replacement at Position 228 Induces Fluctuation in the Ω-Loop of KPC-3 and Reduces the Affinity against Oxyimino Cephalosporins: Kinetic and Molecular Dynamics Studies

Catalysts ◽  
2020 ◽  
Vol 10 (12) ◽  
pp. 1474
Author(s):  
Alessandra Piccirilli ◽  
Fabrizia Brisdelli ◽  
Jean Denis Docquier ◽  
Massimiliano Aschi ◽  
Sabrina Cherubini ◽  
...  
Keyword(s):  
Public Health ◽  
Molecular Dynamics ◽  
Amino Acid ◽  
Active Site ◽  
Md Simulations ◽  
Amino Acid Replacement ◽  
Saturation Mutagenesis ◽  
Active Site Residue ◽  
Class A

KPC enzymes are the most common class A carbapenemases globally diffused. The peculiarity of this family of β-lactamases is represented by their ability to hydrolyse all classes of β-lactams, including carbapenems, posing a serious problem to public health. In the present study, seven laboratory mutants of KPC-3 (D228S, D228W, D228M, D228K, D228L, D228I and D228G) were generated by site-saturation mutagenesis to explore the role of residue 228, a non-active site residue. Compared to KPC-3, the seven mutants showed evident differences in kcat and Km values calculated for some penicillins, cephalosporins and carbapenems. In particular, D228S and D228M showed a significant increase of Km values for cefotaxime and ceftazidime. Circular dichroism (CD) experiments have demonstrated that substitution at position 228 does not affect the secondary structure of the mutants. Molecular dynamics (MD) simulations were performed on KPC-3, D228S and D228M uncomplexed and complexed with cefotaxime (substrate). Although the residue 228 is located far from the active site, between α11 helix and β7 sheet in the opposite site of the Ω-loop, amino acid substitution at this position generates mechanical effects in the active site resulting in enzyme activity changes.

Important roles of hydrophobic interactions in folding and charge interactions in misfolding of α-helix bundle protein

RSC Advances ◽  
2015 ◽  
Vol 5 (6) ◽  
pp. 4191-4199 ◽  
Author(s):  
Qiang Shao
Keyword(s):  
Molecular Dynamics ◽  
Molecular Dynamics Simulation ◽  
Hydrophobic Interactions ◽  
Dynamics Simulation ◽  
Enhanced Sampling ◽  
Helix Bundle ◽  
Α Helix ◽  
Bundle Protein ◽  
Charge Interactions

An enhanced-sampling molecular dynamics simulation is presented to quantitatively demonstrate the important roles of hydrophobic and charge interactions in the folding and misfolding of α-helix bundle protein, respectively.

Efficient Treatment of Fixed and Induced Dipolar Interactions

2000 ◽  
Vol 653 ◽  
Author(s):  
Celeste Sagui ◽  
Thoma Darden
Keyword(s):  
Molecular Dynamics ◽  
Md Simulations ◽  
Lagrangian Formalism ◽  
Dipolar Interactions ◽  
Time Step ◽  
Efficient Treatment ◽  
Particle Mesh Ewald ◽  
Fixed Charges ◽  
Self Consistency ◽  
Induced Dipoles

AbstractFixed and induced point dipoles have been implemented in the Ewald and Particle-Mesh Ewald (PME) formalisms. During molecular dynamics (MD) the induced dipoles can be propagated along with the atomic positions either by interation to self-consistency at each time step, or by a Car-Parrinello (CP) technique using an extended Lagrangian formalism. The use of PME for electrostatics of fixed charges and induced dipoles together with a CP treatment of dipole propagation in MD simulations leads to a cost overhead of only 33% above that of MD simulations using standard PME with fixed charges, allowing the study of polarizability in largemacromolecular systems.

Sign in / Sign up

Export Citation Format

Share Document