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Biomolecules
Volume 4
Issue 1
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Biomolecules, Volume 4, Issue 1 (March 2014) – 18 articles , Pages 1-373

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554 KiB  
Review
Kinetics and Thermodynamics of Membrane Protein Folding
by Ernesto A. Roman and F. Luis González Flecha
Biomolecules 2014, 4(1), 354-373; https://doi.org/10.3390/biom4010354 - 18 Mar 2014
Cited by 22 | Viewed by 14038
Abstract
Understanding protein folding has been one of the great challenges in biochemistry and molecular biophysics. Over the past 50 years, many thermodynamic and kinetic studies have been performed addressing the stability of globular proteins. In comparison, advances in the membrane protein folding field [...] Read more.
Understanding protein folding has been one of the great challenges in biochemistry and molecular biophysics. Over the past 50 years, many thermodynamic and kinetic studies have been performed addressing the stability of globular proteins. In comparison, advances in the membrane protein folding field lag far behind. Although membrane proteins constitute about a third of the proteins encoded in known genomes, stability studies on membrane proteins have been impaired due to experimental limitations. Furthermore, no systematic experimental strategies are available for folding these biomolecules in vitro. Common denaturing agents such as chaotropes usually do not work on helical membrane proteins, and ionic detergents have been successful denaturants only in few cases. Refolding a membrane protein seems to be a craftsman work, which is relatively straightforward for transmembrane β-barrel proteins but challenging for α-helical membrane proteins. Additional complexities emerge in multidomain membrane proteins, data interpretation being one of the most critical. In this review, we will describe some recent efforts in understanding the folding mechanism of membrane proteins that have been reversibly refolded allowing both thermodynamic and kinetic analysis. This information will be discussed in the context of current paradigms in the protein folding field. Full article
(This article belongs to the Special Issue Protein Folding and Misfolding)
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863 KiB  
Review
Re-Configuration of Sphingolipid Metabolism by Oncogenic Transformation
by Anthony S. Don, Xin Y. Lim and Timothy A. Couttas
Biomolecules 2014, 4(1), 315-353; https://doi.org/10.3390/biom4010315 - 14 Mar 2014
Cited by 34 | Viewed by 12627
Abstract
The sphingolipids are one of the major lipid families in eukaryotes, incorporating a diverse array of structural variants that exert a powerful influence over cell fate and physiology. Increased expression of sphingosine kinase 1 (SPHK1), which catalyses the synthesis of the pro-survival, pro-angiogenic [...] Read more.
The sphingolipids are one of the major lipid families in eukaryotes, incorporating a diverse array of structural variants that exert a powerful influence over cell fate and physiology. Increased expression of sphingosine kinase 1 (SPHK1), which catalyses the synthesis of the pro-survival, pro-angiogenic metabolite sphingosine 1-phosphate (S1P), is well established as a hallmark of multiple cancers. Metabolic alterations that reduce levels of the pro-apoptotic lipid ceramide, particularly its glucosylation by glucosylceramide synthase (GCS), have frequently been associated with cancer drug resistance. However, the simple notion that the balance between ceramide and S1P, often referred to as the sphingolipid rheostat, dictates cell survival contrasts with recent studies showing that highly potent and selective SPHK1 inhibitors do not affect cancer cell proliferation or survival, and studies demonstrating higher ceramide levels in some metastatic cancers. Recent reports have implicated other sphingolipid metabolic enzymes such as acid sphingomyelinase (ASM) more strongly in cancer pathogenesis, and highlight lysosomal sphingolipid metabolism as a possible weak point for therapeutic targeting in cancer. This review describes the evidence implicating different sphingolipid metabolic enzymes and their products in cancer pathogenesis, and suggests how newer systems-level approaches may improve our overall understanding of how oncogenic transformation reconfigures sphingolipid metabolism. Full article
(This article belongs to the Special Issue Focus Update in Biomolecules)
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241 KiB  
Review
Detecting Selection on Protein Stability through Statistical Mechanical Models of Folding and Evolution
by Ugo Bastolla
Biomolecules 2014, 4(1), 291-314; https://doi.org/10.3390/biom4010291 - 07 Mar 2014
Cited by 13 | Viewed by 6364
Abstract
The properties of biomolecules depend both on physics and on the evolutionary process that formed them. These two points of view produce a powerful synergism. Physics sets the stage and the constraints that molecular evolution has to obey, and evolutionary theory helps in [...] Read more.
The properties of biomolecules depend both on physics and on the evolutionary process that formed them. These two points of view produce a powerful synergism. Physics sets the stage and the constraints that molecular evolution has to obey, and evolutionary theory helps in rationalizing the physical properties of biomolecules, including protein folding thermodynamics. To complete the parallelism, protein thermodynamics is founded on the statistical mechanics in the space of protein structures, and molecular evolution can be viewed as statistical mechanics in the space of protein sequences. In this review, we will integrate both points of view, applying them to detecting selection on the stability of the folded state of proteins. We will start discussing positive design, which strengthens the stability of the folded against the unfolded state of proteins. Positive design justifies why statistical potentials for protein folding can be obtained from the frequencies of structural motifs. Stability against unfolding is easier to achieve for longer proteins. On the contrary, negative design, which consists in destabilizing frequently formed misfolded conformations, is more difficult to achieve for longer proteins. The folding rate can be enhanced by strengthening short-range native interactions, but this requirement contrasts with negative design, and evolution has to trade-off between them. Finally, selection can accelerate functional movements by favoring low frequency normal modes of the dynamics of the native state that strongly correlate with the functional conformation change. Full article
(This article belongs to the Special Issue Protein Folding and Misfolding)
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Editorial
Acknowledgement to Reviewers of Biomolecules in 2013
by Biomolecules Editorial Office
Biomolecules 2014, 4(1), 289-290; https://doi.org/10.3390/biom4010289 - 04 Mar 2014
Viewed by 3590
Abstract
The editors of Biomolecules would like to express their sincere gratitude to the following reviewers for assessing manuscripts in 2013. [...] Full article
1628 KiB  
Article
Similar Structures to the E-to-H Helix Unit in the Globin-Like Fold are Found in Other Helical Folds
by Masanari Matsuoka, Aoi Fujita, Yosuke Kawai and Takeshi Kikuchi
Biomolecules 2014, 4(1), 268-288; https://doi.org/10.3390/biom4010268 - 27 Feb 2014
Cited by 7 | Viewed by 8122
Abstract
A protein in the globin-like fold contains six alpha-helices, A, B, E, F, G and H. Among them, the E-to-H helix unit (E, F, G and H helices) forms a compact structure. In this study, we searched similar structures to the E-to-H helix [...] Read more.
A protein in the globin-like fold contains six alpha-helices, A, B, E, F, G and H. Among them, the E-to-H helix unit (E, F, G and H helices) forms a compact structure. In this study, we searched similar structures to the E-to-H helix of leghomoglobin in the whole protein structure space using the Dali program. Several similar structures were found in other helical folds, such as KaiA/RbsU domain and Type III secretion system domain. These observations suggest that the E-to-H helix unit may be a common subunit in the whole protein 3D structure space. In addition, the common conserved hydrophobic residues were found among the similar structures to the E-to-H helix unit. Hydrophobic interactions between the conserved residues may stabilize the 3D structures of the unit. We also predicted the possible compact regions of the units using the average distance method. Full article
(This article belongs to the Special Issue Protein Folding and Misfolding)
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452 KiB  
Review
Heavy Metals and Metalloids As a Cause for Protein Misfolding and Aggregation
by Markus J. Tamás, Sandeep K. Sharma, Sebastian Ibstedt, Therese Jacobson and Philipp Christen
Biomolecules 2014, 4(1), 252-267; https://doi.org/10.3390/biom4010252 - 25 Feb 2014
Cited by 329 | Viewed by 16408
Abstract
While the toxicity of metals and metalloids, like arsenic, cadmium, mercury, lead and chromium, is undisputed, the underlying molecular mechanisms are not entirely clear. General consensus holds that proteins are the prime targets; heavy metals interfere with the physiological activity of specific, particularly [...] Read more.
While the toxicity of metals and metalloids, like arsenic, cadmium, mercury, lead and chromium, is undisputed, the underlying molecular mechanisms are not entirely clear. General consensus holds that proteins are the prime targets; heavy metals interfere with the physiological activity of specific, particularly susceptible proteins, either by forming a complex with functional side chain groups or by displacing essential metal ions in metalloproteins. Recent studies have revealed an additional mode of metal action targeted at proteins in a non-native state; certain heavy metals and metalloids have been found to inhibit the in vitro refolding of chemically denatured proteins, to interfere with protein folding in vivo and to cause aggregation of nascent proteins in living cells. Apparently, unfolded proteins with motile backbone and side chains are considerably more prone to engage in stable, pluridentate metal complexes than native proteins with their well-defined 3D structure. By interfering with the folding process, heavy metal ions and metalloids profoundly affect protein homeostasis and cell viability. This review describes how heavy metals impede protein folding and promote protein aggregation, how cells regulate quality control systems to protect themselves from metal toxicity and how metals might contribute to protein misfolding disorders. Full article
(This article belongs to the Special Issue Protein Folding and Misfolding)
1232 KiB  
Review
Refolding Techniques for Recovering Biologically Active Recombinant Proteins from Inclusion Bodies
by Hiroshi Yamaguchi and Masaya Miyazaki
Biomolecules 2014, 4(1), 235-251; https://doi.org/10.3390/biom4010235 - 20 Feb 2014
Cited by 199 | Viewed by 26038
Abstract
Biologically active proteins are useful for studying the biological functions of genes and for the development of therapeutic drugs and biomaterials in a biotechnology industry. Overexpression of recombinant proteins in bacteria, such as Escherichia coli, often results in the formation of inclusion [...] Read more.
Biologically active proteins are useful for studying the biological functions of genes and for the development of therapeutic drugs and biomaterials in a biotechnology industry. Overexpression of recombinant proteins in bacteria, such as Escherichia coli, often results in the formation of inclusion bodies, which are protein aggregates with non-native conformations. As inclusion bodies contain relatively pure and intact proteins, protein refolding is an important process to obtain active recombinant proteins from inclusion bodies. However, conventional refolding methods, such as dialysis and dilution, are time consuming and, often, recovered yields of active proteins are low, and a trial-and-error process is required to achieve success. Recently, several approaches have been reported to refold these aggregated proteins into an active form. The strategies largely aim at reducing protein aggregation during the refolding procedure. This review focuses on protein refolding techniques using chemical additives and laminar flow in microfluidic chips for the efficient recovery of active proteins from inclusion bodies. Full article
(This article belongs to the Special Issue Protein Folding and Misfolding)
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1017 KiB  
Review
Structure and Function of the Bi-Directional Bacterial Flagellar Motor
by Yusuke V. Morimoto and Tohru Minamino
Biomolecules 2014, 4(1), 217-234; https://doi.org/10.3390/biom4010217 - 18 Feb 2014
Cited by 99 | Viewed by 19981
Abstract
The bacterial flagellum is a locomotive organelle that propels the bacterial cell body in liquid environments. The flagellum is a supramolecular complex composed of about 30 different proteins and consists of at least three parts: a rotary motor, a universal joint, and a [...] Read more.
The bacterial flagellum is a locomotive organelle that propels the bacterial cell body in liquid environments. The flagellum is a supramolecular complex composed of about 30 different proteins and consists of at least three parts: a rotary motor, a universal joint, and a helical filament. The flagellar motor of Escherichia coli and Salmonella enterica is powered by an inward-directed electrochemical potential difference of protons across the cytoplasmic membrane. The flagellar motor consists of a rotor made of FliF, FliG, FliM and FliN and a dozen stators consisting of MotA and MotB. FliG, FliM and FliN also act as a molecular switch, enabling the motor to spin in both counterclockwise and clockwise directions. Each stator is anchored to the peptidoglycan layer through the C-terminal periplasmic domain of MotB and acts as a proton channel to couple the proton flow through the channel with torque generation. Highly conserved charged residues at the rotor–stator interface are required not only for torque generation but also for stator assembly around the rotor. In this review, we will summarize our current understanding of the structure and function of the proton-driven bacterial flagellar motor. Full article
(This article belongs to the Special Issue Focus Update in Biomolecules)
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654 KiB  
Review
Transient Non-Native Helix Formation during the Folding of β-Lactoglobulin
by Masamichi Ikeguchi
Biomolecules 2014, 4(1), 202-216; https://doi.org/10.3390/biom4010202 - 13 Feb 2014
Cited by 13 | Viewed by 7493
Abstract
In ideal proteins, only native interactions are stabilized step-by-step in a smooth funnel-like energy landscape. In real proteins, however, the transient formation of non-native structures is frequently observed. In this review, the transient formation of non-native structures is described using the non-native helix [...] Read more.
In ideal proteins, only native interactions are stabilized step-by-step in a smooth funnel-like energy landscape. In real proteins, however, the transient formation of non-native structures is frequently observed. In this review, the transient formation of non-native structures is described using the non-native helix formation during the folding of β-lactoglobulin as a prominent example. Although β-lactoglobulin is a predominantly β-sheet protein, it has been shown to form non-native helices during the early stage of folding. The location of non-native helices, their stabilization mechanism, and their role in the folding reaction are discussed. Full article
(This article belongs to the Special Issue Protein Folding and Misfolding)
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1373 KiB  
Article
Molecular Dynamics Simulations Capture the Misfolding of the Bovine Prion Protein at Acidic pH
by Chin Jung Cheng and Valerie Daggett
Biomolecules 2014, 4(1), 181-201; https://doi.org/10.3390/biom4010181 - 10 Feb 2014
Cited by 22 | Viewed by 9195
Abstract
Bovine spongiform encephalopathy (BSE), or mad cow disease, is a fatal neurodegenerative disease that is transmissible to humans and that is currently incurable. BSE is caused by the prion protein (PrP), which adopts two conformers; PrPC is the native innocuous form, which [...] Read more.
Bovine spongiform encephalopathy (BSE), or mad cow disease, is a fatal neurodegenerative disease that is transmissible to humans and that is currently incurable. BSE is caused by the prion protein (PrP), which adopts two conformers; PrPC is the native innocuous form, which is α-helix rich; and PrPSc is the β-sheet rich misfolded form, which is infectious and forms neurotoxic species. Acidic pH induces the conversion of PrPC to PrPSc. We have performed molecular dynamics simulations of bovine PrP at various pH regimes. An acidic pH environment induced conformational changes that were not observed in neutral pH simulations. Putative misfolded structures, with nonnative β-strands formed in the flexible N-terminal domain, were found in acidic pH simulations. Two distinct pathways were observed for the formation of nonnative β-strands: at low pH, hydrophobic contacts with M129 nucleated the nonnative β-strand; at mid-pH, polar contacts involving Q168 and D178 facilitated the formation of a hairpin at the flexible N-terminus. These mid- and low pH simulations capture the process of nonnative β-strand formation, thereby improving our understanding of how PrPC misfolds into the β-sheet rich PrPSc and how pH factors into the process. Full article
(This article belongs to the Special Issue Protein Folding and Misfolding)
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567 KiB  
Article
Reconstructing Protein Structures by Neural Network Pairwise Interaction Fields and Iterative Decoy Set Construction
by Claudio Mirabello, Alessandro Adelfio and Gianluca Pollastri
Biomolecules 2014, 4(1), 160-180; https://doi.org/10.3390/biom4010160 - 10 Feb 2014
Cited by 2 | Viewed by 6752
Abstract
Predicting the fold of a protein from its amino acid sequence is one of the grand problems in computational biology. While there has been progress towards a solution, especially when a protein can be modelled based on one or more known structures (templates), [...] Read more.
Predicting the fold of a protein from its amino acid sequence is one of the grand problems in computational biology. While there has been progress towards a solution, especially when a protein can be modelled based on one or more known structures (templates), in the absence of templates, even the best predictions are generally much less reliable. In this paper, we present an approach for predicting the three-dimensional structure of a protein from the sequence alone, when templates of known structure are not available. This approach relies on a simple reconstruction procedure guided by a novel knowledge-based evaluation function implemented as a class of artificial neural networks that we have designed: Neural Network Pairwise Interaction Fields (NNPIF). This evaluation function takes into account the contextual information for each residue and is trained to identify native-like conformations from non-native-like ones by using large sets of decoys as a training set. The training set is generated and then iteratively expanded during successive folding simulations. As NNPIF are fast at evaluating conformations, thousands of models can be processed in a short amount of time, and clustering techniques can be adopted for model selection. Although the results we present here are very preliminary, we consider them to be promising, with predictions being generated at state-of-the-art levels in some of the cases. Full article
(This article belongs to the Special Issue Protein Folding and Misfolding)
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746 KiB  
Article
Analysis of Guanine Oxidation Products in Double-Stranded DNA and Proposed Guanine Oxidation Pathways in Single-Stranded, Double-Stranded or Quadruplex DNA
by Masayuki Morikawa, Katsuhito Kino, Takanori Oyoshi, Masayo Suzuki, Takanobu Kobayashi and Hiroshi Miyazawa
Biomolecules 2014, 4(1), 140-159; https://doi.org/10.3390/biom4010140 - 10 Feb 2014
Cited by 34 | Viewed by 8371
Abstract
Guanine is the most easily oxidized among the four DNA bases, and some guanine-rich sequences can form quadruplex structures. In a previous study using 6-mer DNA d(TGGGGT), which is the shortest oligomer capable of forming quadruplex structures, we demonstrated that guanine oxidation products [...] Read more.
Guanine is the most easily oxidized among the four DNA bases, and some guanine-rich sequences can form quadruplex structures. In a previous study using 6-mer DNA d(TGGGGT), which is the shortest oligomer capable of forming quadruplex structures, we demonstrated that guanine oxidation products of quadruplex DNA differ from those of single-stranded DNA. Therefore, the hotooxidation products of double-stranded DNA (dsDNA) may also differ from that of quadruplex or single-stranded DNA, with the difference likely explaining the influence of DNA structures on guanine oxidation pathways. In this study, the guanine oxidation products of the dsDNA d(TGGGGT)/d(ACCCCA) were analyzed using HPLC and electrospray ionization-mass spectrometry (ESI-MS). As a result, the oxidation products in this dsDNA were identified as 2,5-diamino-4H-imidazol-4-one (Iz), 8-oxo-7,8-dihydroguanine (8oxoG), dehydroguanidinohydantoin (Ghox), and guanidinohydantoin (Gh). The major oxidation products in dsDNA were consistent with a combination of each major oxidation product observed in single-stranded and quadruplex DNA. We previously reported that the kinds of the oxidation products in single-stranded or quadruplex DNA depend on the ease of deprotonation of the guanine radical cation (G•+) at the N1 proton. Similarly, this mechanism was also involved in dsDNA. Deprotonation in dsDNA is easier than in quadruplex DNA and more difficult in single-stranded DNA, which can explain the formation of the four oxidation products in dsDNA. Full article
(This article belongs to the Special Issue Focus Update in Biomolecules)
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310 KiB  
Review
Microbial Enzymes: Tools for Biotechnological Processes
by Jose L. Adrio and Arnold L. Demain
Biomolecules 2014, 4(1), 117-139; https://doi.org/10.3390/biom4010117 - 16 Jan 2014
Cited by 527 | Viewed by 31838
Abstract
Microbial enzymes are of great importance in the development of industrial bioprocesses. Current applications are focused on many different markets including pulp and paper, leather, detergents and textiles, pharmaceuticals, chemical, food and beverages, biofuels, animal feed and personal care, among others. Today there [...] Read more.
Microbial enzymes are of great importance in the development of industrial bioprocesses. Current applications are focused on many different markets including pulp and paper, leather, detergents and textiles, pharmaceuticals, chemical, food and beverages, biofuels, animal feed and personal care, among others. Today there is a need for new, improved or/and more versatile enzymes in order to develop more novel, sustainable and economically competitive production processes. Microbial diversity and modern molecular techniques, such as metagenomics and genomics, are being used to discover new microbial enzymes whose catalytic properties can be improved/modified by different strategies based on rational, semi-rational and random directed evolution. Most industrial enzymes are recombinant forms produced in bacteria and fungi. Full article
(This article belongs to the Special Issue Enzymes and Their Biotechnological Applications)
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523 KiB  
Review
Effect of Metals on Kinetic Pathways of Amyloid-β Aggregation
by Francis Hane and Zoya Leonenko
Biomolecules 2014, 4(1), 101-116; https://doi.org/10.3390/biom4010101 - 10 Jan 2014
Cited by 94 | Viewed by 12303
Abstract
Metal ions, including copper and zinc, have been implicated in the pathogenesis of Alzheimer’s disease through a variety of mechanisms including increased amyloid-β affinity and redox effects. Recent reports have demonstrated that the amyloid-β monomer does not necessarily travel through a definitive intermediary [...] Read more.
Metal ions, including copper and zinc, have been implicated in the pathogenesis of Alzheimer’s disease through a variety of mechanisms including increased amyloid-β affinity and redox effects. Recent reports have demonstrated that the amyloid-β monomer does not necessarily travel through a definitive intermediary en-route to a stable amyloid fibril structure. Rather, amyloid-β misfolding may follow a variety of pathways resulting in a fibrillar end-product or a variety of oligomeric end-products with a diversity of structures and sizes. The presence of metal ions has been demonstrated to alter the kinetic pathway of the amyloid-β peptide which may lead to more toxic oligomeric end-products. In this work, we review the contemporary literature supporting the hypothesis that metal ions alter the reaction pathway of amyloid-β misfolding leading to more neurotoxic species. Full article
(This article belongs to the Special Issue Metal Binding Proteins)
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569 KiB  
Review
Long Noncoding RNAs in Imprinting and X Chromosome Inactivation
by Joseph M. Autuoro, Stephan P. Pirnie and Gordon G. Carmichael
Biomolecules 2014, 4(1), 76-100; https://doi.org/10.3390/biom4010076 - 07 Jan 2014
Cited by 52 | Viewed by 11108
Abstract
The field of long noncoding RNA (lncRNA) research has been rapidly advancing in recent years. Technological advancements and deep-sequencing of the transcriptome have facilitated the identification of numerous new lncRNAs, many with unusual properties, however, the function of most of these molecules is [...] Read more.
The field of long noncoding RNA (lncRNA) research has been rapidly advancing in recent years. Technological advancements and deep-sequencing of the transcriptome have facilitated the identification of numerous new lncRNAs, many with unusual properties, however, the function of most of these molecules is still largely unknown. Some evidence suggests that several of these lncRNAs may regulate their own transcription in cis, and that of nearby genes, by recruiting remodeling factors to local chromatin. Notably, lncRNAs are known to exist at many imprinted gene clusters. Genomic imprinting is a complex and highly regulated process resulting in the monoallelic silencing of certain genes, based on the parent-of-origin of the allele. It is thought that lncRNAs may regulate many imprinted loci, however, the mechanism by which they exert such influence is poorly understood. This review will discuss what is known about the lncRNAs of major imprinted loci, and the roles they play in the regulation of imprinting. Full article
(This article belongs to the Special Issue Focus Update in Biomolecules)
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307 KiB  
Article
A Firefly-Inspired Method for Protein Structure Prediction in Lattice Models
by Brian Maher, Andreas A. Albrecht, Martin Loomes, Xin-She Yang and Kathleen Steinhöfel
Biomolecules 2014, 4(1), 56-75; https://doi.org/10.3390/biom4010056 - 07 Jan 2014
Cited by 25 | Viewed by 8552
Abstract
We introduce a Firefly-inspired algorithmic approach for protein structure prediction over two different lattice models in three-dimensional space. In particular, we consider three-dimensional cubic and three-dimensional face-centred-cubic (FCC) lattices. The underlying energy models are the Hydrophobic-Polar (H-P) model, the Miyazawa–Jernigan (M-J) model and [...] Read more.
We introduce a Firefly-inspired algorithmic approach for protein structure prediction over two different lattice models in three-dimensional space. In particular, we consider three-dimensional cubic and three-dimensional face-centred-cubic (FCC) lattices. The underlying energy models are the Hydrophobic-Polar (H-P) model, the Miyazawa–Jernigan (M-J) model and a related matrix model. The implementation of our approach is tested on ten H-P benchmark problems of a length of 48 and ten M-J benchmark problems of a length ranging from 48 until 61. The key complexity parameter we investigate is the total number of objective function evaluations required to achieve the optimum energy values for the H-P model or competitive results in comparison to published values for the M-J model. For H-P instances and cubic lattices, where data for comparison are available, we obtain an average speed-up over eight instances of 2.1, leaving out two extreme values (otherwise, 8.8). For six M-J instances, data for comparison are available for cubic lattices and runs with a population size of 100, where, a priori, the minimum free energy is a termination criterion. The average speed-up over four instances is 1.2 (leaving out two extreme values, otherwise 1.1), which is achieved for a population size of only eight instances. The present study is a test case with initial results for ad hoc parameter settings, with the aim of justifying future research on larger instances within lattice model settings, eventually leading to the ultimate goal of implementations for off-lattice models. Full article
(This article belongs to the Special Issue Protein Folding and Misfolding)
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873 KiB  
Review
Misfolding of Amyloidogenic Proteins and Their Interactions with Membranes
by Annalisa Relini, Nadia Marano and Alessandra Gliozzi
Biomolecules 2014, 4(1), 20-55; https://doi.org/10.3390/biom4010020 - 27 Dec 2013
Cited by 22 | Viewed by 8986
Abstract
In this paper, we discuss amyloidogenic proteins, their misfolding, resulting structures, and interactions with membranes, which lead to membrane damage and subsequent cell death. Many of these proteins are implicated in serious illnesses such as Alzheimer’s disease and Parkinson’s disease. Misfolding of amyloidogenic [...] Read more.
In this paper, we discuss amyloidogenic proteins, their misfolding, resulting structures, and interactions with membranes, which lead to membrane damage and subsequent cell death. Many of these proteins are implicated in serious illnesses such as Alzheimer’s disease and Parkinson’s disease. Misfolding of amyloidogenic proteins leads to the formation of polymorphic oligomers and fibrils. Oligomeric aggregates are widely thought to be the toxic species, however, fibrils also play a role in membrane damage. We focus on the structure of these aggregates and their interactions with model membranes. Study of interactions of amlyoidogenic proteins with model and natural membranes has shown the importance of the lipid bilayer in protein misfolding and aggregation and has led to the development of several models for membrane permeabilization by the resulting amyloid aggregates. We discuss several of these models: formation of structured pores by misfolded amyloidogenic proteins, extraction of lipids, interactions with receptors in biological membranes, and membrane destabilization by amyloid aggregates perhaps analogous to that caused by antimicrobial peptides. Full article
(This article belongs to the Special Issue Protein Folding and Misfolding)
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6685 KiB  
Article
The Role of Non-Native Interactions in the Folding of Knotted Proteins: Insights from Molecular Dynamics Simulations
by Roberto Covino, Tatjana Škrbić, Silvio A Beccara, Pietro Faccioli and Cristian Micheletti
Biomolecules 2014, 4(1), 1-19; https://doi.org/10.3390/biom4010001 - 24 Dec 2013
Cited by 26 | Viewed by 7285
Abstract
For several decades, the presence of knots in naturally-occurring proteins was largely ruled out a priori for its supposed incompatibility with the efficiency and robustness of folding processes. For this very same reason, the later discovery of several unrelated families of knotted proteins [...] Read more.
For several decades, the presence of knots in naturally-occurring proteins was largely ruled out a priori for its supposed incompatibility with the efficiency and robustness of folding processes. For this very same reason, the later discovery of several unrelated families of knotted proteins motivated researchers to look into the physico-chemical mechanisms governing the concerted sequence of folding steps leading to the consistent formation of the same knot type in the same protein location. Besides experiments, computational studies are providing considerable insight into these mechanisms. Here, we revisit a number of such recent investigations within a common conceptual and methodological framework. By considering studies employing protein models with different structural resolution (coarse-grained or atomistic) and various force fields (from pure native-centric to realistic atomistic ones), we focus on the role of native and non-native interactions. For various unrelated instances of knotted proteins, non-native interactions are shown to be very important for favoring the emergence of conformations primed for successful self-knotting events. Full article
(This article belongs to the Special Issue Protein Folding and Misfolding)
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