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Open AccessArticle

Effects of Pressure and Temperature on the Atomic Fluctuations of Dihydrofolate Reductase from a Psychropiezophile and a Mesophile

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Int. J. Mol. Sci. 2019, 20(6), 1452; https://doi.org/10.3390/ijms20061452 - 22 Mar 2019

Cited by 7 | Viewed by 1987

Abstract

Determining the effects of extreme conditions on proteins from “extremophilic” and mesophilic microbes is important for understanding how life adapts to living at extremes as well as how extreme conditions can be used for sterilization and food preservation. Previous molecular dynamics simulations of [...] Read more.

Determining the effects of extreme conditions on proteins from “extremophilic” and mesophilic microbes is important for understanding how life adapts to living at extremes as well as how extreme conditions can be used for sterilization and food preservation. Previous molecular dynamics simulations of dihydrofolate reductase (DHFR) from a psychropiezophile (cold- and pressure-loving), Moritella profunda (Mp), and a mesophile, Escherichia coli (Ec), at various pressures and temperatures indicate that atomic fluctuations, which are important for enzyme function, increase with both temperature and pressure. Here, the factors that cause increases in atomic fluctuations in the simulations are examined. The fluctuations increase with temperature not only because of greater thermal energy and thermal expansion of the protein but also because hydrogen bonds between protein atoms are weakened. However, the increase in fluctuations with pressure cannot be due to thermal energy, which remains constant, nor the compressive effects of pressure, but instead, the hydrogen bonds are also weakened. In addition, increased temperature causes larger increases in fluctuations of the loop regions of MpDHFR than EcDHFR, and increased pressure causes both increases and decreases in fluctuations of the loops, which differ between the two. Full article

(This article belongs to the Special Issue Protein Structural Dynamics)

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Open AccessArticle

Multi-Spectroscopic Characterization of Human Serum Albumin Binding with Cyclobenzaprine Hydrochloride: Insights from Biophysical and In Silico Approaches

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Int. J. Mol. Sci. 2019, 20(3), 662; https://doi.org/10.3390/ijms20030662 - 03 Feb 2019

Cited by 33 | Viewed by 3660

Abstract

Cyclobenzaprine hydrochloride (CBH) is a well-known muscle relaxant that is widely used to relieve muscle spasms and other pain associated with acute musculoskeletal conditions. In this study, we elucidated the binding characteristics of this muscle relaxant to human serum albumin (HSA). From a [...] Read more.

Cyclobenzaprine hydrochloride (CBH) is a well-known muscle relaxant that is widely used to relieve muscle spasms and other pain associated with acute musculoskeletal conditions. In this study, we elucidated the binding characteristics of this muscle relaxant to human serum albumin (HSA). From a pharmaceutical and biochemical viewpoint, insight into the structure, functions, dynamics, and features of HSA-CBH complex holds great importance. The binding of CBH with this major circulatory transport protein was studied using a combination of biophysical approaches such as UV-VIS absorption, fluorescence quenching, and circular dichroism (CD) spectroscopy. Various in silico techniques, molecular docking and molecular dynamics, were also used to gain deeper insight into the binding. A reduction in the fluorescence intensities of HSA-CBH complex with a constant increase in temperature, revealed the static mode of protein fluorescence quenching upon CBH addition, which confirmed the formation of the HSA-CBH ground state complex. The alteration in the UV-VIS and far-UV CD spectrum indicated changes in both secondary and tertiary structures of HSA upon binding of CBH, further proving CBH binding to HSA. The analysis of thermodynamic parameters ∆H° and ∆S° showed that binding of CBH to HSA was dominated by intermolecular hydrophobic forces. The results of the molecular docking and molecular dynamics simulation studies also confirmed the stability of the complex and supported the experimental results. Full article

(This article belongs to the Special Issue Protein Structural Dynamics)

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Open AccessArticle

Serological Number for Characterization of Circulating Antibodies

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Andrea Palermo

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Alexander Nesterov-Mueller

Int. J. Mol. Sci. 2019, 20(3), 604; https://doi.org/10.3390/ijms20030604 - 30 Jan 2019

Cited by 3 | Viewed by 2699

Abstract

The dissociation constant of the circulating IgG antibodies is suggested to be proportional to the partial concentrations of these antibodies in blood serum in equilibrium. This coefficient, called serological number, is a dimensionless parameter and may be equal for all antibodies in a [...] Read more.

The dissociation constant of the circulating IgG antibodies is suggested to be proportional to the partial concentrations of these antibodies in blood serum in equilibrium. This coefficient, called serological number, is a dimensionless parameter and may be equal for all antibodies in a serum. Based on the serological number, we derived the equilibrium equation of the humoral immune system which allows estimating the number of different binding motifs in a serum. This equation also allows estimating the number of binding motifs of posttranslational and conformational nature. The feasibility of measuring the serological number via peptide arrays was demonstrated. Fifteen peptides with unique binding motifs were incubated and stained with the blood serum of a healthy adult at different dilutions. From these experiments, the serological number was determined. The serological number may explain the pre-existing antibody response after vaccination. Full article

(This article belongs to the Special Issue Protein Structural Dynamics)

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Open AccessArticle

Mutations Utilize Dynamic Allostery to Confer Resistance in TEM-1 β-lactamase

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Tushar Modi

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S. Banu Ozkan

Int. J. Mol. Sci. 2018, 19(12), 3808; https://doi.org/10.3390/ijms19123808 - 29 Nov 2018

Cited by 24 | Viewed by 3190

Abstract

β-lactamases are enzymes produced by bacteria to hydrolyze β-lactam antibiotics as a common mechanism of resistance. Evolution in such enzymes has been rendering a wide variety of antibiotics impotent, therefore posing a major threat. Clinical and in vitro studies of evolution in TEM-1 [...] Read more.

β-lactamases are enzymes produced by bacteria to hydrolyze β-lactam antibiotics as a common mechanism of resistance. Evolution in such enzymes has been rendering a wide variety of antibiotics impotent, therefore posing a major threat. Clinical and in vitro studies of evolution in TEM-1 β-lactamase have revealed a large number of single point mutations that are responsible for driving resistance to antibiotics and/or inhibitors. The distal locations of these mutations from the active sites suggest that these allosterically modulate the antibiotic resistance. We investigated the effects of resistance driver mutations on the conformational dynamics of the enzyme to provide insights about the mechanism of their long-distance interactions. Through all-atom molecular dynamics (MD) simulations, we obtained the dynamic flexibility profiles of the variants and compared those with that of the wild type TEM-1. While the mutational sites in the variants did not have any direct van der Waals interactions with the active site position S70 and E166, we observed a change in the flexibility of these sites, which play a very critical role in hydrolysis. Such long distance dynamic interactions were further confirmed by dynamic coupling index (DCI) analysis as the sites involved in resistance driving mutations exhibited high dynamic coupling with the active sites. A more exhaustive dynamic analysis, using a selection pressure for ampicillin and cefotaxime resistance on all possible types of substitutions in the amino acid sequence of TEM-1, further demonstrated the observed mechanism. Mutational positions that play a crucial role for the emergence of resistance to new antibiotics exhibited high dynamic coupling with the active site irrespective of their locations. These dynamically coupled positions were neither particularly rigid nor particularly flexible, making them more evolvable positions. Nature utilizes these sites to modulate the dynamics of the catalytic sites instead of mutating the highly rigid positions around the catalytic site. Full article

(This article belongs to the Special Issue Protein Structural Dynamics)

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Open AccessArticle

Regulation of Protein Structural Changes by Incorporation of a Small-Molecule Linker

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Youngmin Kim

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Cheolhee Yang

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Tae Wu Kim

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Kamatchi Thamilselvan

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Yonggwan Kim

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Hyotcherl Ihee

Int. J. Mol. Sci. 2018, 19(12), 3714; https://doi.org/10.3390/ijms19123714 - 22 Nov 2018

Cited by 1 | Viewed by 2539

Abstract

Proteins have the potential to serve as nanomachines with well-controlled structural movements, and artificial control of their conformational changes is highly desirable for successful applications exploiting their dynamic structural characteristics. Here, we demonstrate an experimental approach for regulating the degree of conformational change [...] Read more.

Proteins have the potential to serve as nanomachines with well-controlled structural movements, and artificial control of their conformational changes is highly desirable for successful applications exploiting their dynamic structural characteristics. Here, we demonstrate an experimental approach for regulating the degree of conformational change in proteins by incorporating a small-molecule linker into a well-known photosensitive protein, photoactive yellow protein (PYP), which is sensitized by blue light and undergoes a photo-induced N-terminal protrusion coupled with chromophore-isomerization-triggered conformational changes. Specifically, we introduced thiol groups into specific sites of PYP through site-directed mutagenesis and then covalently conjugated a small-molecule linker into these sites, with the expectation that the linker is likely to constrain the structural changes associated with the attached positions. To investigate the structural dynamics of PYP incorporated with the small-molecule linker (SML-PYP), we employed the combination of small-angle X-ray scattering (SAXS), transient absorption (TA) spectroscopy and experiment-restrained rigid-body molecular dynamics (MD) simulation. Our results show that SML-PYP exhibits much reduced structural changes during photo-induced signaling as compared to wild-type PYP. This demonstrates that incorporating an external molecular linker can limit photo-induced structural dynamics of the protein and may be used as a strategy for fine control of protein structural dynamics in nanomachines. Full article

(This article belongs to the Special Issue Protein Structural Dynamics)

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Open AccessArticle

Revealing Unknown Protein Structures Using Computational Conformational Sampling Guided by Experimental Hydrogen-Exchange Data

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Didier Devaurs

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Dinler A. Antunes

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Lydia E. Kavraki

Int. J. Mol. Sci. 2018, 19(11), 3406; https://doi.org/10.3390/ijms19113406 - 31 Oct 2018

Cited by 2 | Viewed by 2290

Abstract

Both experimental and computational methods are available to gather information about a protein’s conformational space and interpret changes in protein structure. However, experimentally observing and computationally modeling large proteins remain critical challenges for structural biology. Our work aims at addressing these challenges by [...] Read more.

Both experimental and computational methods are available to gather information about a protein’s conformational space and interpret changes in protein structure. However, experimentally observing and computationally modeling large proteins remain critical challenges for structural biology. Our work aims at addressing these challenges by combining computational and experimental techniques relying on each other to overcome their respective limitations. Indeed, despite its advantages, an experimental technique such as hydrogen-exchange monitoring cannot produce structural models because of its low resolution. Additionally, the computational methods that can generate such models suffer from the curse of dimensionality when applied to large proteins. Adopting a common solution to this issue, we have recently proposed a framework in which our computational method for protein conformational sampling is biased by experimental hydrogen-exchange data. In this paper, we present our latest application of this computational framework: generating an atomic-resolution structural model for an unknown protein state. For that, starting from an available protein structure, we explore the conformational space of this protein, using hydrogen-exchange data on this unknown state as a guide. We have successfully used our computational framework to generate models for three proteins of increasing size, the biggest one undergoing large-scale conformational changes. Full article

(This article belongs to the Special Issue Protein Structural Dynamics)

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Open AccessArticle

Adsorption of Fibronectin Fragment on Surfaces Using Fully Atomistic Molecular Dynamics Simulations

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Evangelos Liamas

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Karina Kubiak-Ossowska

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Int. J. Mol. Sci. 2018, 19(11), 3321; https://doi.org/10.3390/ijms19113321 - 25 Oct 2018

Cited by 19 | Viewed by 3098

Abstract

The effect of surface chemistry on the adsorption characteristics of a fibronectin fragment (FNIII^8–10) was investigated using fully atomistic molecular dynamics simulations. Model surfaces were constructed to replicate self-assembled monolayers terminated with methyl, hydroxyl, amine, and carboxyl moieties. It was found [...] Read more.

The effect of surface chemistry on the adsorption characteristics of a fibronectin fragment (FNIII^8–10) was investigated using fully atomistic molecular dynamics simulations. Model surfaces were constructed to replicate self-assembled monolayers terminated with methyl, hydroxyl, amine, and carboxyl moieties. It was found that adsorption of FNIII^8–10 on charged surfaces is rapid, specific, and driven by electrostatic interactions, and that the anchoring residues are either polar uncharged or of opposing charge to that of the targeted surfaces. On charged surfaces the presence of a strongly bound layer of water molecules and ions hinders FNIII^8–10 adsorption. In contrast, adsorption kinetics on uncharged surfaces are slow and non-specific, as they are driven by van der Waals interactions, and the anchoring residues are polar uncharged. Due to existence of a positively charged area around its cell-binding region, FNIII^8–10 is available for subsequent cell binding when adsorbed on a positively charged surface, but not when adsorbed on a negatively charged surface. On uncharged surfaces, the availability of the fibronectin fragment’s cell-binding region is not clearly distinguished because adsorption is much less specific. Full article

(This article belongs to the Special Issue Protein Structural Dynamics)

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Open AccessArticle

Exploring Configuration Space and Path Space of Biomolecules Using Enhanced Sampling Techniques—Searching for Mechanism and Kinetics of Biomolecular Functions

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Hiroshi Fujisaki

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Kei Moritsugu

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Yasuhiro Matsunaga

Int. J. Mol. Sci. 2018, 19(10), 3177; https://doi.org/10.3390/ijms19103177 - 15 Oct 2018

Cited by 2 | Viewed by 2892

Abstract

To understand functions of biomolecules such as proteins, not only structures but their conformational change and kinetics need to be characterized, but its atomistic details are hard to obtain both experimentally and computationally. Here, we review our recent computational studies using novel enhanced [...] Read more.

To understand functions of biomolecules such as proteins, not only structures but their conformational change and kinetics need to be characterized, but its atomistic details are hard to obtain both experimentally and computationally. Here, we review our recent computational studies using novel enhanced sampling techniques for conformational sampling of biomolecules and calculations of their kinetics. For efficiently characterizing the free energy landscape of a biomolecule, we introduce the multiscale enhanced sampling method, which uses a combined system of atomistic and coarse-grained models. Based on the idea of Hamiltonian replica exchange, we can recover the statistical properties of the atomistic model without any biases. We next introduce the string method as a path search method to calculate the minimum free energy pathways along a multidimensional curve in high dimensional space. Finally we introduce novel methods to calculate kinetics of biomolecules based on the ideas of path sampling: one is the Onsager–Machlup action method, and the other is the weighted ensemble method. Some applications of the above methods to biomolecular systems are also discussed and illustrated. Full article

(This article belongs to the Special Issue Protein Structural Dynamics)

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Open AccessArticle

Conformational Dynamics of Herpesviral NEC Proteins in Different Oligomerization States

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Int. J. Mol. Sci. 2018, 19(10), 2908; https://doi.org/10.3390/ijms19102908 - 25 Sep 2018

Cited by 6 | Viewed by 3188

Abstract

All herpesviruses use a heterodimeric nuclear egress complex (NEC) to transport capsids out of host cell nuclei. Despite their overall similar structure, NECs may differ significantly in sequence between different viruses. Up to now, structural information is limited to isolated NEC heterodimers and [...] Read more.

All herpesviruses use a heterodimeric nuclear egress complex (NEC) to transport capsids out of host cell nuclei. Despite their overall similar structure, NECs may differ significantly in sequence between different viruses. Up to now, structural information is limited to isolated NEC heterodimers and to large hexagonal lattices made up of hexagonal ring-like structures (“Hexagons”). The present study aimed to expand the existing structural knowledge with information on the dynamics of NECs from different viruses and in different oligomerization states. For this task, comparative molecular dynamics simulations were performed of the free NEC heterodimers from three different viruses (HCMV (human cytomegalovirus), HSV-1 (herpes simplex virus 1), and PRV (pseudorabies virus)). In addition, higher oligomerization states comprising two or six NEC heterodimers were characterized for HCMV and HSV-1. The study revealed that the isolated NEC heterodimers from α- (HSV-1, PRV) and β-herpesviruses (HCMV) differ significantly in their dynamics, which can be attributed to a poorly conserved interface region between the NEC subdomains. These differences become smaller for higher oligomerization states, and both HCMV and HSV-1 individual Hexagons exhibit a common region of enhanced dynamics, which might be of functional relevance for the formation of curved vesicle structures or the recognition of hexameric capsid proteins. Full article

(This article belongs to the Special Issue Protein Structural Dynamics)

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Open AccessArticle

Anti-Correlation between the Dynamics of the Active Site Loop and C-Terminal Tail in Relation to the Homodimer Asymmetry of the Mouse Erythroid 5-Aminolevulinate Synthase

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Int. J. Mol. Sci. 2018, 19(7), 1899; https://doi.org/10.3390/ijms19071899 - 28 Jun 2018

Cited by 6 | Viewed by 2717

Abstract

Biosynthesis of heme represents a complex process that involves multiple stages controlled by different enzymes. The first of these proteins is a pyridoxal 5′-phosphate (PLP)-dependent homodimeric enzyme, 5-aminolevulinate synthase (ALAS), that catalyzes the rate-limiting step in heme biosynthesis, the condensation of glycine with [...] Read more.

Biosynthesis of heme represents a complex process that involves multiple stages controlled by different enzymes. The first of these proteins is a pyridoxal 5′-phosphate (PLP)-dependent homodimeric enzyme, 5-aminolevulinate synthase (ALAS), that catalyzes the rate-limiting step in heme biosynthesis, the condensation of glycine with succinyl-CoA. Genetic mutations in human erythroid-specific ALAS (ALAS2) are associated with two inherited blood disorders, X-linked sideroblastic anemia (XLSA) and X-linked protoporphyria (XLPP). XLSA is caused by diminished ALAS2 activity leading to decreased ALA and heme syntheses and ultimately ineffective erythropoiesis, whereas XLPP results from “gain-of-function” ALAS2 mutations and consequent overproduction of protoporphyrin IX and increase in Zn²⁺-protoporphyrin levels. All XLPP-linked mutations affect the intrinsically disordered C-terminal tail of ALAS2. Our earlier molecular dynamics (MD) simulation-based analysis showed that the activity of ALAS2 could be regulated by the conformational flexibility of the active site loop whose structural features and dynamics could be changed due to mutations. We also revealed that the dynamic behavior of the two protomers of the ALAS2 dimer differed. However, how the structural dynamics of ALAS2 active site loop and C-terminal tail dynamics are related to each other and contribute to the homodimer asymmetry remained unanswered questions. In this study, we used bioinformatics and computational biology tools to evaluate the role(s) of the C-terminal tail dynamics in the structure and conformational dynamics of the murine ALAS2 homodimer active site loop. To assess the structural correlation between these two regions, we analyzed their structural displacements and determined their degree of correlation. Here, we report that the dynamics of ALAS2 active site loop is anti-correlated with the dynamics of the C-terminal tail and that this anti-correlation can represent a molecular basis for the functional and dynamic asymmetry of the ALAS2 homodimer. Full article

(This article belongs to the Special Issue Protein Structural Dynamics)

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Open AccessArticle

Nonnative Energetic Frustrations in Protein Folding at Residual Level: A Simulation Study of Homologous Immunoglobulin-like β-Sandwich Proteins

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Yunxiang Sun

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Feng Ding

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Dengming Ming

Int. J. Mol. Sci. 2018, 19(5), 1515; https://doi.org/10.3390/ijms19051515 - 18 May 2018

Viewed by 3158

Abstract

Nonnative interactions cause energetic frustrations in protein folding and were found to dominate key events in folding intermediates. However, systematically characterizing energetic frustrations that are caused by nonnative intra-residue interactions at residual resolution is still lacking. Recently, we studied the folding of a [...] Read more.

Nonnative interactions cause energetic frustrations in protein folding and were found to dominate key events in folding intermediates. However, systematically characterizing energetic frustrations that are caused by nonnative intra-residue interactions at residual resolution is still lacking. Recently, we studied the folding of a set of homologous all-α proteins and found that nonnative-contact-based energetic frustrations are highly correlated to topology of the protein native-contact network. Here, we studied the folding of nine homologous immunoglobulin-like (Ig-like) β-sandwich proteins, and examined nonnative-contact-based energetic frustrations Gō-like model. Our calculations showed that nonnative-interaction-based energetic frustrations in β-sandwich proteins are much more complicated than those in all-

α

proteins, and they exhibit highly heterogeneous effects on the folding of secondary structures. Further, the nonnative interactions introduced distinct correlations in the folding of different folding-patches of β-sandwich proteins. Taken together, a strong interplay might exist between nonnative-interaction energetic frustrations and the protein native-contact networks, which ensures that β-sandwich domains adopt a common folding mechanism. Full article

(This article belongs to the Special Issue Protein Structural Dynamics)

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Open AccessArticle

Conformational Dynamics and Stability of U-Shaped and S-Shaped Amyloid β Assemblies

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Int. J. Mol. Sci. 2018, 19(2), 571; https://doi.org/10.3390/ijms19020571 - 14 Feb 2018

Cited by 28 | Viewed by 3891

Abstract

Alzheimer’s disease is the most fatal neurodegenerative disorder characterized by the aggregation and deposition of Amyloid β (Aβ) oligomers in the brain of patients. Two principal variants of Aβ exist in humans: Aβ_1–40 and Aβ_1–42. The former is the most [...] Read more.

Alzheimer’s disease is the most fatal neurodegenerative disorder characterized by the aggregation and deposition of Amyloid β (Aβ) oligomers in the brain of patients. Two principal variants of Aβ exist in humans: Aβ_1–40 and Aβ_1–42. The former is the most abundant in the plaques, while the latter is the most toxic species and forms fibrils more rapidly. Interestingly, fibrils of Aβ_1–40 peptides can only assume U-shaped conformations while Aβ_1–42 can also arrange as S-shaped three-stranded chains, as recently discovered. As alterations in protein conformational arrangement correlate with cell toxicity and speed of disease progression, it is important to characterize, at molecular level, the conformational dynamics of amyloid fibrils. In this work, Replica Exchange Molecular Dynamics simulations were carried out to compare the conformational dynamics of U-shaped and S-shaped Aβ_17–42 small fibrils. Our computational results provide support for the stability of the recently proposed S-shaped model due to the maximized interactions involving the C-terminal residues. On the other hand, the U-shaped motif is characterized by significant distortions resulting in a more disordered assembly. Outcomes of our work suggest that the molecular architecture of the protein aggregates might play a pivotal role in formation and conformational stability of the resulting fibrils. Full article

(This article belongs to the Special Issue Protein Structural Dynamics)

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Review

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Coarse-Grained Protein Dynamics Studies Using Elastic Network Models

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Yuichi Togashi

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Holger Flechsig

Int. J. Mol. Sci. 2018, 19(12), 3899; https://doi.org/10.3390/ijms19123899 - 05 Dec 2018

Cited by 22 | Viewed by 3604

Abstract

Elastic networks have been used as simple models of proteins to study their slow structural dynamics. They consist of point-like particles connected by linear Hookean springs and hence are convenient for linear normal mode analysis around a given reference structure. Furthermore, dynamic simulations [...] Read more.

Elastic networks have been used as simple models of proteins to study their slow structural dynamics. They consist of point-like particles connected by linear Hookean springs and hence are convenient for linear normal mode analysis around a given reference structure. Furthermore, dynamic simulations using these models can provide new insights. As the computational cost associated with these models is considerably lower compared to that of all-atom models, they are also convenient for comparative studies between multiple protein structures. In this review, we introduce examples of coarse-grained molecular dynamics studies using elastic network models and their derivatives, focusing on the nonlinear phenomena, and discuss their applicability to large-scale macromolecular assemblies. Full article

(This article belongs to the Special Issue Protein Structural Dynamics)

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Protein Structural Dynamics of Wild-Type and Mutant Homodimeric Hemoglobin Studied by Time-Resolved X-Ray Solution Scattering

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Srinivasan Muniyappan

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Int. J. Mol. Sci. 2018, 19(11), 3633; https://doi.org/10.3390/ijms19113633 - 18 Nov 2018

Cited by 7 | Viewed by 2814

Abstract

The quaternary transition between the relaxed (R) and tense (T) states of heme-binding proteins is a textbook example for the allosteric structural transition. Homodimeric hemoglobin (HbI) from Scapharca inaequivalvis is a useful model system for investigating the allosteric behavior because of the relatively [...] Read more.

The quaternary transition between the relaxed (R) and tense (T) states of heme-binding proteins is a textbook example for the allosteric structural transition. Homodimeric hemoglobin (HbI) from Scapharca inaequivalvis is a useful model system for investigating the allosteric behavior because of the relatively simple quaternary structure. To understand the cooperative transition of HbI, wild-type and mutants of HbI have been studied by using time-resolved X-ray solution scattering (TRXSS), which is sensitive to the conformational changes. Herein, we review the structural dynamics of HbI investigated by TRXSS and compare the results of TRXSS with those of other techniques. Full article

(This article belongs to the Special Issue Protein Structural Dynamics)

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Transient Secondary Structures as General Target-Binding Motifs in Intrinsically Disordered Proteins

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Do-Hyoung Kim

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Kyou-Hoon Han

Int. J. Mol. Sci. 2018, 19(11), 3614; https://doi.org/10.3390/ijms19113614 - 15 Nov 2018

Cited by 24 | Viewed by 2910

Abstract

Intrinsically disordered proteins (IDPs) are unorthodox proteins that do not form three-dimensional structures under non-denaturing conditions, but perform important biological functions. In addition, IDPs are associated with many critical diseases including cancers, neurodegenerative diseases, and viral diseases. Due to the generic name of [...] Read more.

Intrinsically disordered proteins (IDPs) are unorthodox proteins that do not form three-dimensional structures under non-denaturing conditions, but perform important biological functions. In addition, IDPs are associated with many critical diseases including cancers, neurodegenerative diseases, and viral diseases. Due to the generic name of “unstructured” proteins used for IDPs in the early days, the notion that IDPs would be completely unstructured down to the level of secondary structures has prevailed for a long time. During the last two decades, ample evidence has been accumulated showing that IDPs in their target-free state are pre-populated with transient secondary structures critical for target binding. Nevertheless, such a message did not seem to have reached with sufficient clarity to the IDP or protein science community largely because similar but different expressions were used to denote the fundamentally same phenomenon of presence of such transient secondary structures, which is not surprising for a quickly evolving field. Here, we summarize the critical roles that these transient secondary structures play for diverse functions of IDPs by describing how various expressions referring to transient secondary structures have been used in different contexts. Full article

(This article belongs to the Special Issue Protein Structural Dynamics)

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Modeling of Protein Structural Flexibility and Large-Scale Dynamics: Coarse-Grained Simulations and Elastic Network Models

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Sebastian Kmiecik

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Maksim Kouza

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Aleksandra E. Badaczewska-Dawid

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Andrzej Kloczkowski

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Andrzej Kolinski

Int. J. Mol. Sci. 2018, 19(11), 3496; https://doi.org/10.3390/ijms19113496 - 06 Nov 2018

Cited by 45 | Viewed by 6707

Abstract

Fluctuations of protein three-dimensional structures and large-scale conformational transitions are crucial for the biological function of proteins and their complexes. Experimental studies of such phenomena remain very challenging and therefore molecular modeling can be a good alternative or a valuable supporting tool for [...] Read more.

Fluctuations of protein three-dimensional structures and large-scale conformational transitions are crucial for the biological function of proteins and their complexes. Experimental studies of such phenomena remain very challenging and therefore molecular modeling can be a good alternative or a valuable supporting tool for the investigation of large molecular systems and long-time events. In this minireview, we present two alternative approaches to the coarse-grained (CG) modeling of dynamic properties of protein systems. We discuss two CG representations of polypeptide chains used for Monte Carlo dynamics simulations of protein local dynamics and conformational transitions, and highly simplified structure-based elastic network models of protein flexibility. In contrast to classical all-atom molecular dynamics, the modeling strategies discussed here allow the quite accurate modeling of much larger systems and longer-time dynamic phenomena. We briefly describe the main features of these models and outline some of their applications, including modeling of near-native structure fluctuations, sampling of large regions of the protein conformational space, or possible support for the structure prediction of large proteins and their complexes. Full article

(This article belongs to the Special Issue Protein Structural Dynamics)

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Role of Computational Methods in Going beyond X-ray Crystallography to Explore Protein Structure and Dynamics

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Int. J. Mol. Sci. 2018, 19(11), 3401; https://doi.org/10.3390/ijms19113401 - 30 Oct 2018

Cited by 38 | Viewed by 6535

Abstract

Protein structural biology came a long way since the determination of the first three-dimensional structure of myoglobin about six decades ago. Across this period, X-ray crystallography was the most important experimental method for gaining atomic-resolution insight into protein structures. However, as the role [...] Read more.

Protein structural biology came a long way since the determination of the first three-dimensional structure of myoglobin about six decades ago. Across this period, X-ray crystallography was the most important experimental method for gaining atomic-resolution insight into protein structures. However, as the role of dynamics gained importance in the function of proteins, the limitations of X-ray crystallography in not being able to capture dynamics came to the forefront. Computational methods proved to be immensely successful in understanding protein dynamics in solution, and they continue to improve in terms of both the scale and the types of systems that can be studied. In this review, we briefly discuss the limitations of X-ray crystallography in studying protein dynamics, and then provide an overview of different computational methods that are instrumental in understanding the dynamics of proteins and biomacromolecular complexes. Full article

(This article belongs to the Special Issue Protein Structural Dynamics)

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Overview of the Maturation Machinery of the H-Cluster of [FeFe]-Hydrogenases with a Focus on HydF

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Int. J. Mol. Sci. 2018, 19(10), 3118; https://doi.org/10.3390/ijms19103118 - 11 Oct 2018

Cited by 15 | Viewed by 2754

Abstract

Hydrogen production in nature is performed by hydrogenases. Among them, [FeFe]-hydrogenases have a peculiar active site, named H-cluster, that is made of two parts, synthesized in different pathways. The cubane sub-cluster requires the normal iron-sulfur cluster maturation machinery. The [2Fe] sub-cluster instead requires [...] Read more.

Hydrogen production in nature is performed by hydrogenases. Among them, [FeFe]-hydrogenases have a peculiar active site, named H-cluster, that is made of two parts, synthesized in different pathways. The cubane sub-cluster requires the normal iron-sulfur cluster maturation machinery. The [2Fe] sub-cluster instead requires a dedicated set of maturase proteins, HydE, HydF, and HydG that work to assemble the cluster and deliver it to the apo-hydrogenase. In particular, the delivery is performed by HydF. In this review, we will perform an overview of the latest knowledge on the maturation machinery of the H-cluster, focusing in particular on HydF. Full article

(This article belongs to the Special Issue Protein Structural Dynamics)

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