Jingjing Guo

Exploring the Influence of Carbon Nanoparticles on the Formation of β-Sheet-Rich Oligomers of IAPP22–28 Peptide by Molecular Dynamics Simulation

Recent advances in nanotechnologies have led to wide use of nanomaterials in biomedical field. However, nanoparticles are found to interfere with protein misfolding and aggregation associated with many human diseases. It is still a controversial issue whether nanoparticles inhibit or promote protein aggregation. In this study, we used molecular dynamics simulations to explore the effects of three kinds of carbon nanomaterials including graphene, carbon nanotube and C60 on the aggregation behavior of islet amyloid polypeptide fragment 22–28 (IAPP22–28). The diverse behaviors of IAPP22–28 peptides on the surfaces of carbon nanomaterials were studied. The results suggest these nanomaterials can prevent β-sheet formation in differing degrees and further affect the aggregation of IAPP22–28. The π–π stacking and hydrophobic interactions are different in the interactions between peptides and different nanoparticles. The subtle differences in the interaction are due to the difference in surface curvature and area. The results demonstrate the adsorption interaction has competitive advantages over the interactions between peptides. Therefore, the fibrillation of IAPP22–28 may be inhibited at its early stage by graphene or SWCNT. Our study can not only enhance the understanding about potential effects of nanomaterials to amyloid formation, but also provide valuable information to develop potential β-sheet formation inhibitors against type II diabetes.

Influence of the pathogenic mutations T188K/R/A on the structural stability and misfolding of human prion protein: Insight from molecular dynamics simulations

BACKGROUND Prion diseases are associated with a conformational switch for PrP from PrP(C) to PrP(Sc). Many genetic mutations are linked with prion diseases, such as mutations T188K/R/A with fCJD. SCOPE OF REVIEW MD simulations for the WT PrP and its mutants were performed to explore the underlying dynamic effects of T188 mutations on human PrP. Although the globular domains are fairly conserved, the three mutations have diverse effects on the dynamics properties of PrP, including the shift of H1, the elongation of native β-sheet and the conversion of S2-H2 loop to a 3(10) helix. MAJOR CONCLUSIONS Our present study indicates that the three mutants for PrP may undergo different pathogenic mechanisms and the realistic atomistic simulations can provide insights into the effects of disease-associated mutations on PrP dynamics and stability, which can enhance our understanding of how mutations induce the conversion from PrP(C) to PrP(Sc). General significance Our present study helps to understand the effects of T188K/R/A mutations on human PrP: despite the three pathogenic mutations almost do not alter the native structure of PrP, but perturb its stability. This instability may further modulate the oligomerization pathways and determine the features of the PrP(Sc) assemblies.

Exploring the influence of EGCG on the β-sheet-rich oligomers of human islet amyloid polypeptide (hIAPP1-37) and identifying its possible binding sites from molecular dynamics simulation.

EGCG possesses the ability of disaggregating the existing amyloid fibrils which were associated with many age-related degenerative diseases. However, the molecular mechanism of EGCG to disaggregate these fibrils is poorly known. In this work, to study the influence of EGCG on the full-length human islet amyloid polypeptide 1–37 (hIAPP1–37) oligomers, molecular dynamics simulations of hIAPP1–37 pentamer and decamer with EGCG were performed, respectively. The obtained results indicate that EGCG indeed destabilized the hIAPP1–37 oligomers. The nematic order parameter and secondary structure calculations coupled with the free-energy landscape indicate that EGCG broke the initial ordered pattern of two polymers, greatly reduced their β-sheet content and enlarged their conformational space. On this basis, three possible target sites were identified with the binding capacity order of S1>S2>S3. After a deeper analysis of each site, we found that S1 was the most possible site on which residues B-Ile26/Ala25, A-Phe23, B/C-Leu27 and E-Tyr37 played an important role for their binding. The proposal of this molecular mechanism can not only provide a prospective interaction figure between EGCG and β-sheet-rich fibrils of hIAPP1–37, but also is useful for further discovering other potential inhibitors.

The adsorption mechanism and induced conformational changes of three typical proteins with different secondary structural features on graphene

Nanomaterials (NMs) have been widely used in the biomedical field. To explore the biological effects of graphene as one of the most widely used NMs, we studied the adsorption behavior and induced conformational changes of proteins representing different secondary structures on graphene: β-strands (WW domain), mixed α/β structure (BBA protein), and α-helices (λ-repressor). Our results indicate these model proteins were adsorbed onto the graphene surface quickly and tightly, however, varied degrees of conformational changes were observed. During the adsorption process, we found the β motif is a stiffer structural unit than the α-helix. Moreover, the level of conformational changes of the proteins is related not only to their sequence and structural properties but also to their orientation. Overall, from the different levels of intermolecular interaction, the protein adsorption was driven by van der Waals, hydrophobic and π–π stacking interactions. Our work suggests that classical molecular dynamics simulations and MM-GBSA calculations can provide useful information about the dynamics and energetics of the adsorption of proteins onto graphene. We believe that these findings will help us to further understand the adsorption of proteins on hydrophobic carbon nanomaterials at the atomic level.

Molecular mechanism of the enhanced virulence of 2009 pandemic influenza A (H1N1) virus from D222G mutation in the hemagglutinin: a molecular modeling study.

AbstractD222G mutation of the hemagglutinin (HA) is of special interest because of its close association with the enhanced virulence of 2009 pandemic influenza A (H1N1) virus through the increased binding affinity to α2,3-linked sialylated glycan receptors. However, there is still a lack of detailed understanding about the molecular mechanism of this enhanced virulence. Here, molecular dynamics simulation and binding free energy calculation were performed to explore the altered glycan receptor binding mechanism of HA upon the D222G mutation by studying the interaction of one α2,3-linked sialylglycan (sequence: SIA-GAL-NAG) with the wild type and D222G mutated HA. The binding free energy calculation based on the molecular mechanics generalized Born surface area (MM-GBSA) method indicates that the D222G mutated HA has a much stronger binding affinity with the studied α2,3-linked glycan than the wild type. This is consistent with the experimental result. The increased binding free energy of D222G mutant mainly comes from the increased energy contribution of Gln223. The structural analysis proves that the altered electrostatic potential of receptor binding domain (RBD) and the increased flexibility of 220-loop are the essential reasons leading to the increased affinity of HA to α2,3-linked sialic acid glycans. The obtained results of this study have allowed a deeper understanding of the receptor recognition mechanism and the pathogenicity of influenza virus, which will be valuable to the structure-based inhibitors design targeting influenza virus entry process. FigureThe altered α-2,3 linked glycan binding to hemagglutinin upon D222G mutation

Stabilities and structures of islet amyloid polypeptide (IAPP22-28) oligomers: from dimer to 16-mer.

BACKGROUND The formation of amyloid fibrils is associated with many age-related degenerative diseases. Nevertheless, the molecular mechanism that directs the nucleation of these fibrils is not fully understood. METHODS Here, we performed MD simulations for the NFGAILS motif of hIAPP associated with the type II diabetes to estimate the stabilities of hIAPP22-28 protofibrils with different sizes: from 2 to 16 chains. In addition, to study the initial self-assembly stage, 4 and 8 IAPP22-28 chains in explicit solvent were also simulated. RESULTS Our results indicate that the ordered protofibrils with no more than 16 hIAPP22-28 chains will be structurally stable in two layers, while one-layer or three-layer models are not stable as expected. Furthermore, the oligomerization simulations show that the initial coil structures of peptides can quickly aggregate and convert to partially ordered β-sheet-rich oligomers. CONCLUSIONS Based on the obtained results, we found that the stability of an IAPP22-28 oligomer was not only related with its size but also with its morphology. The driving forces to form and stabilize an oligomer are the hydrophobic effects and backbone H-bond interaction. Our simulations also indicate that IAPP22-28 peptides tend to form an antiparallel strand orientation within the sheet. GENERAL SIGNIFICANCE Our finding can not only enhance the understanding about potential mechanisms of hIAPP nuclei formation and the extensive structural polymorphisms of oligomers, but also provide valuable information to develop potential β-sheet formation inhibitors against type II diabetes.

Exploring structural and thermodynamic stabilities of human prion protein pathogenic mutants D202N, E211Q and Q217R

The central event in the pathogenesis of prion protein (PrP) is a profound conformational change from its α-helical (PrP(C)) to its β-sheet-rich isoform (PrP(Sc)). Many single amino acid mutations of PrP are associated with familial prion diseases, such as D202N, E211Q, and Q217R mutations located at the third native α-helix of human PrP. In order to explore the underlying structural and dynamic effects of these mutations, we performed all-atom molecular dynamics (MD) simulations for the wild-type (WT) PrP and its mutants. The obtained results indicate that these amino acid substitutions have subtle effects on the protein structures, but show large changes of the overall electrostatic potential distributions. We can infer that the changes of PrP electrostatic surface due to the studied mutations may influence the intermolecular interactions during the aggregation process. In addition, the mutations also affect the thermodynamic stabilities of PrP.

Structural Diversity and Initial Oligomerization of PrP106–126 Studied by Replica-Exchange and Conventional Molecular Dynamics Simulations

Prion diseases are marked by cerebral accumulation of the abnormal isoform of the prion protein. A fragment of prion protein composed of residues 106–126 (PrP106–126) exhibits similar properties to full length prion and plays a key role in the conformational conversion from cellular prion to its pathogenic pattern. Soluble oligomers of PrP106–126 have been proposed to be responsible for neurotoxicity. However, the monomeric conformational space and initial oligomerization of PrP106–126 are still obscure, which are very important for understanding the conformational conversion of PrP106–126. In this study, replica exchange molecular dynamics simulations were performed to investigate monomeric and dimeric states of PrP106–126 in implicit solvent. The structural diversity of PrP106–126 was observed and this peptide did not acquire stable structure. The dimeric PrP106–126 also displayed structural diversity and hydrophobic interaction drove the dimerization. To further study initial oligomerization of PrP106–126, 1 µs conventional molecular dynamics simulations of trimer and tetramer formation were carried out in implicit solvent. We have observed the spontaneous formation of several basic oligomers and stable oligomers with high β-sheet contents were sampled in the simulations of trimer and tetramer formation. The β-hairpin formed in hydrophobic tail of PrP106–126 with residues 118–120 in turn may stabilize these oligomers and seed the formation oligomers. This study can provide insight into the detailed information about the structure of PrP106–126 and the dynamics of aggregation of monomeric PrP106–126 into oligomers in atomic level.

The role of Cys179–Cys214 disulfide bond in the stability and folding of prion protein: insights from molecular dynamics simulations

AbstractPrion diseases are associated with misfolding and aggregation of prion protein (PrP). Cellular prion protein contains a disulfide bond linking Cys residues at positions 179 and 214. It has been proposed that this disulfide bond plays an important role in the conversion between cellular (PrPC) and the scrapie form of prion protein (PrPSc). To probe the role of this disulfide bond in the stability and folding of prion protein, we employed molecular dynamics simulations to study the reduced prion protein and a variant of PrP in which the two cysteines were replaced by alanines residues. The simulations highlighted the changes that occurred upon breakage of the disulfide bond. Breakage of the disulfide bond resulted in a shift of H1, elongation of the native β-sheet and perturbation of the hydrophobic core of huPrP. The changes are similar to the conformational transitions of prion protein in low pH, in denaturing conditions or with pathogenic mutations, which indicate that rupture of the disulfide bond may lead to the misfolding of prion protein. FigureThe breakage of Cys179-Cys214 disulfide bond resulted in conformational transitions of prion protein

The solvent at antigen-binding site regulated C3d–CR2 interactions through the C-terminal tail of C3d at different ion strengths: insights from molecular dynamics simulation

BACKGROUND The interactions of complement receptor 2 (CR2) and the degradation fragment C3d of complement component C3 play important links between the innate and adaptive immune systems. Due to the importance of C3d-CR2 interaction in the design of vaccines and inhibitors, a number of studies have been performed to investigate C3d-CR2 interaction. Many studies have indicated C3d-CR2 interactions are ionic strength-dependent. METHODS To investigate the molecular mechanism of C3d-CR2 interaction and the origin of effects of ionic strength, molecular dynamics simulations for C3d-CR2 complex together with the energetic and structural analysis were performed. RESULTS Our results revealed the increased interactions between charged protein and ions weaken C3d-CR2 association, as ionic strengths increase. Moreover, ion strengths have similar effects on antigen-binding site and CR2 binding site. Meanwhile, Ala17 and Gln20 will transform between the activated and non-activated states mediated by His133 and Glu135 at different ion strengths. CONCLUSIONS Our results reveal the origins of the effects of ionic strengths on C3d-CR2 interactions are due to the changes of water, ion occupancies and distributions. GENERAL SIGNIFICANCE This study uncovers the origin of the effect of ionic strength on C3d-CR2 interaction and deepens the understanding of the molecular mechanism of their interaction, which is valuable for the design of vaccines and small molecule inhibitors.