Mechanical properties of polymers can be regulated by changing the numbers of hydrogen bonds and entanglement points.However,the interplay between hydrogen bond network and entangled network during stretching has not ...Mechanical properties of polymers can be regulated by changing the numbers of hydrogen bonds and entanglement points.However,the interplay between hydrogen bond network and entangled network during stretching has not been fully studied.We performed molecular dynamics simulations to investigate the changes of hydrogen bonds and entanglements during stretching.The stretching causes the orientation of local segments,leading to the entanglement sliding and disentanglements at different strain regions.Then,the number of entanglement points keeps constant at first and then decreases with increasing strain.Differently,the orientation of local segments can cause the change of chain conformation,which leads to the breakage of hydrogen bonds.Thus,the number of hydrogen bonds decreases with the increase of strain.Simulation results also demonstrated that the number of hydrogen bonds decreases faster during stretching in systems containing more entanglements.In systems with different hydrogen bond site contents,the initial number of entanglement nodes and its decline range during stretching increase firstly and then decrease with the increase of hydrogen bond site content.展开更多
Abstract Conotoxins belong to the large families of disulfide-rich peptide toxins from cone snail venom, and can act on a broad spectrum of ion channels and receptors. They are classified into different subtypes based...Abstract Conotoxins belong to the large families of disulfide-rich peptide toxins from cone snail venom, and can act on a broad spectrum of ion channels and receptors. They are classified into different subtypes based on their targets. The a-conotoxins selectively inhibit the current of the nicotinic acetylcholine receptors. Because of their unique selectivity towards distinct nAChR subtypes, a-conotoxins become valuable tools in nAChR study. In addition to the X-ray structures of a-conotoxins in complex with acetyleholine-binding protein, a homolog of the nAChR ligand-binding domain, the high-resolution crystal structures of the extracellular domain of the al and a9 subunits are also obtained. Such structures not only revealed the details of the configuration of nAChR, but also provided higher sequence identity templates for modeling the binding modes of a-conotoxins to nAChR. This mini-review summarizes recent modeling studies for the determination of the binding modes of a-conotoxins to nAChR. As there are not crystal structures of the nAChR in complex with conotoxins, computational modeling in combination of mutagenesis data is expected to reveal the molecular recognition mechanisms that govern the interactions between a-conotoxins and nAChR at molecular level. An accurate determination of the binding modes of a-conotoxins on AChRs allows rational design of a-conotoxin analogues with improved potency or selectivity to nAChRs.展开更多
Abstract The aggregation of amyloid β-protein （Aβ） is tightly linked to the pathogenesis of Alzheimer＇s disease. Previous studies have found that three peptide inhibitors （i.e., KLVFF, VVIA, and LPFFD） can inhi...Abstract The aggregation of amyloid β-protein （Aβ） is tightly linked to the pathogenesis of Alzheimer＇s disease. Previous studies have found that three peptide inhibitors （i.e., KLVFF, VVIA, and LPFFD） can inhibit Aβ aggregation and alleviate Aβ-induced neurotoxicity. How- ever, atomic details of binding modes and binding affinities between these peptide inhibitors and Aβ have not been revealed. Here, using molecular dynamics simulations and molecular mechanics Poisson Boltzmann surface area （MM/PBSA） analysis, we examined the effect of three peptide inhibitors （KLVFF, VVIA, and LPFFD） on their sequence-specific interactions with Aβ and the molecular basis of their inhibition. All inhibitors exhibit varied binding affinity to Aβ, in which KLVFF has the highest binding affinity, whereas LPFFD has the least. MM/PBSA analysis further revealed that different peptide inhibitors have different modes of interaction with Aβ, consequently hotspot binding residues, and underlying driving forces. Specific residue-based interactions between inhibitors and Aβ were determined and compared for illustrating different binding and inhibition mechanisms. This work provides structure-based binding information for further modifica- tion and optimization of these three peptide inhibitors to enhance their binding and inhibitory abilities against Aβ aggregation.展开更多
Abnormalities in the transition betweenα-helices andβ-sheets(α-βtransition)may lead to devastating neurodegenerative diseases,such as Parkinson's syndrome and Alzheimer's disease.Ionic liquids(ILs)are pote...Abnormalities in the transition betweenα-helices andβ-sheets(α-βtransition)may lead to devastating neurodegenerative diseases,such as Parkinson's syndrome and Alzheimer's disease.Ionic liquids(ILs)are potential drugs for targeted therapies against these diseases because of their excellent bioactivity and designability of ILs.However,the mechanism through which ILs regulate the aα-βtransition remains unclear.Herein,a combination of GPU-accelerated microsecond molecular dynamics simulations,correlation analysis,and machine learning was used to probe the dynamicalα-βtransition process induced by ILs of 1-alkyl-3-methylimidazolium chloride([C_(n)mim]cl)and its molecular mechanism.Interestingly,the cation of [C_(n)mim]+in ILs can spontaneously insert into the peptides as free ions(n≤10)and clusters(n≥11).Such insertion can significantly inhibit theα-β,transition and the inhibiting ability for the clusters is more significant than that of free ions,where[Ciomim]+and[C_(12)mim]+can reduce the maximumβ-sheet content of the peptide by 18.5% and 44.9%,respectively.Furthermore,the correlation analysis and machine learning method were used to develop a predictive model accounting for the influencing factors on theα-βtransition,which could accurately predict the effect of ILs on theα-βtransition.Overall,these quantitative results may not only deepen the understanding of the role of ILs in theα-βtransition but also guide the development of the IL-based treatments for related diseases.展开更多
Nitrogen-doped graphene （NG） was successfully synthesized by a novel, facile, and scalable bottom-up method. The annealed NG （NG-A） possessed high specific surface area and a hierarchical porous texture, and exhib...Nitrogen-doped graphene （NG） was successfully synthesized by a novel, facile, and scalable bottom-up method. The annealed NG （NG-A） possessed high specific surface area and a hierarchical porous texture, and exhibited remarkably improved electrocatalytic activity in the oxygen reduction reaction in both alkaline and acidic media. Ab initio molecular dynamic simulations indicated that rapid H transfer and the thermodynamic stability of six-membered N structures promoted the transformation of N-containing species from pyrrolic to pyridinic at 600 ℃ In O2-staturated 0.1 M KOH solution, the half-wave potential （El/2） of NG-A was only 62 mV lower than that of a commercial Pt/C catalyst, and the limiting current density of NG-A was 0.5 mA.cm-2 larger than that of Pt/C. Koutecky-Levich （K-L） plots and rotating ring-disk electrode measurement indicated a four-electron- transfer pathway in NG-A, which could be ascribed to its high content of pyridinic N.展开更多
Understanding how small molecules interface with amyloid fibrils at the nanoscale is of importance for developing therapeutic treatments against amyloid-based diseases. Here, we show for the first time that human isle...Understanding how small molecules interface with amyloid fibrils at the nanoscale is of importance for developing therapeutic treatments against amyloid-based diseases. Here, we show for the first time that human islet amyloid polypeptides （LAPP） in the fibrillar form are polymorphic, ambidextrous, and possess multiple periodicities. Upon interfacing with the small molecule epigallocatechin gallate （EGCG）, IAPP aggregation was rendered off-pathway and assumed a form with soft and disordered clusters, while mature IAPP fibrils displayed kinks and branching but conserved the twisted fibril morphology. These nanoscale phenomena resulted from competitive interactions between EGCG and the IAPP amyloidogenic region, as well as end capping of the fibrils by the small molecule. This information is crucial in delineating IAPP toxicity implicated in type 2 diabetes and for developing new inhibitors against amyloidogenesis.展开更多
基金This work was financially supported by the National Natural Science Foundation of China(No.52173020)Jiangsu Funding Program for Excellent Postdoctoral Talent(No.2024ZB545)Qing Lan Project of Jiangsu Province of China(No.[2022]29).
文摘Mechanical properties of polymers can be regulated by changing the numbers of hydrogen bonds and entanglement points.However,the interplay between hydrogen bond network and entangled network during stretching has not been fully studied.We performed molecular dynamics simulations to investigate the changes of hydrogen bonds and entanglements during stretching.The stretching causes the orientation of local segments,leading to the entanglement sliding and disentanglements at different strain regions.Then,the number of entanglement points keeps constant at first and then decreases with increasing strain.Differently,the orientation of local segments can cause the change of chain conformation,which leads to the breakage of hydrogen bonds.Thus,the number of hydrogen bonds decreases with the increase of strain.Simulation results also demonstrated that the number of hydrogen bonds decreases faster during stretching in systems containing more entanglements.In systems with different hydrogen bond site contents,the initial number of entanglement nodes and its decline range during stretching increase firstly and then decrease with the increase of hydrogen bond site content.
基金supported by the National Natural Science Foundation of China (81502977 to Dr. Yu R. and 81373322 to Dr. Jiang T.)China Postdoctoral Science Foundation funded project (No.861505020050 for Dr. Yu R.)+1 种基金Special Foundation for Qingdao Basic Research Program (15-9-1-85-jch)Fundamental Research Funds for the Central Universities (No.841512007 for Dr. Yu R.)
文摘Abstract Conotoxins belong to the large families of disulfide-rich peptide toxins from cone snail venom, and can act on a broad spectrum of ion channels and receptors. They are classified into different subtypes based on their targets. The a-conotoxins selectively inhibit the current of the nicotinic acetylcholine receptors. Because of their unique selectivity towards distinct nAChR subtypes, a-conotoxins become valuable tools in nAChR study. In addition to the X-ray structures of a-conotoxins in complex with acetyleholine-binding protein, a homolog of the nAChR ligand-binding domain, the high-resolution crystal structures of the extracellular domain of the al and a9 subunits are also obtained. Such structures not only revealed the details of the configuration of nAChR, but also provided higher sequence identity templates for modeling the binding modes of a-conotoxins to nAChR. This mini-review summarizes recent modeling studies for the determination of the binding modes of a-conotoxins to nAChR. As there are not crystal structures of the nAChR in complex with conotoxins, computational modeling in combination of mutagenesis data is expected to reveal the molecular recognition mechanisms that govern the interactions between a-conotoxins and nAChR at molecular level. An accurate determination of the binding modes of a-conotoxins on AChRs allows rational design of a-conotoxin analogues with improved potency or selectivity to nAChRs.
文摘Abstract The aggregation of amyloid β-protein （Aβ） is tightly linked to the pathogenesis of Alzheimer＇s disease. Previous studies have found that three peptide inhibitors （i.e., KLVFF, VVIA, and LPFFD） can inhibit Aβ aggregation and alleviate Aβ-induced neurotoxicity. How- ever, atomic details of binding modes and binding affinities between these peptide inhibitors and Aβ have not been revealed. Here, using molecular dynamics simulations and molecular mechanics Poisson Boltzmann surface area （MM/PBSA） analysis, we examined the effect of three peptide inhibitors （KLVFF, VVIA, and LPFFD） on their sequence-specific interactions with Aβ and the molecular basis of their inhibition. All inhibitors exhibit varied binding affinity to Aβ, in which KLVFF has the highest binding affinity, whereas LPFFD has the least. MM/PBSA analysis further revealed that different peptide inhibitors have different modes of interaction with Aβ, consequently hotspot binding residues, and underlying driving forces. Specific residue-based interactions between inhibitors and Aβ were determined and compared for illustrating different binding and inhibition mechanisms. This work provides structure-based binding information for further modifica- tion and optimization of these three peptide inhibitors to enhance their binding and inhibitory abilities against Aβ aggregation.
基金the National Natural Science Foundation of China(21834006,22078322,21978293,and 21978027)the Youth Innovation Promotion Association of CAS(2021046,Y2021046)State Key Laboratory of Treatments and Recycling for Organic Effluents by Adsorption in Petroleum and Chemical Industry(SDHY2114).
文摘Abnormalities in the transition betweenα-helices andβ-sheets(α-βtransition)may lead to devastating neurodegenerative diseases,such as Parkinson's syndrome and Alzheimer's disease.Ionic liquids(ILs)are potential drugs for targeted therapies against these diseases because of their excellent bioactivity and designability of ILs.However,the mechanism through which ILs regulate the aα-βtransition remains unclear.Herein,a combination of GPU-accelerated microsecond molecular dynamics simulations,correlation analysis,and machine learning was used to probe the dynamicalα-βtransition process induced by ILs of 1-alkyl-3-methylimidazolium chloride([C_(n)mim]cl)and its molecular mechanism.Interestingly,the cation of [C_(n)mim]+in ILs can spontaneously insert into the peptides as free ions(n≤10)and clusters(n≥11).Such insertion can significantly inhibit theα-β,transition and the inhibiting ability for the clusters is more significant than that of free ions,where[Ciomim]+and[C_(12)mim]+can reduce the maximumβ-sheet content of the peptide by 18.5% and 44.9%,respectively.Furthermore,the correlation analysis and machine learning method were used to develop a predictive model accounting for the influencing factors on theα-βtransition,which could accurately predict the effect of ILs on theα-βtransition.Overall,these quantitative results may not only deepen the understanding of the role of ILs in theα-βtransition but also guide the development of the IL-based treatments for related diseases.
基金This work is financially supported by Shanghai Institute of Ceramics, the One Hundred Talent Plan of Chinese Academy of Sciences, National Natural Science Foundation of China （No. 21307145）, Key Project for Young Researcher of State Key Laboratory of High Performance Ceramics and Superfine Microstructure, the Youth Science and Technology Talents ＂Sail＂ Program of Shanghai Municipal Science and Technology Commission （No. 15YF1413800）, and the research grant （No. 14DZ2261200） from Shanghai government.
文摘Nitrogen-doped graphene （NG） was successfully synthesized by a novel, facile, and scalable bottom-up method. The annealed NG （NG-A） possessed high specific surface area and a hierarchical porous texture, and exhibited remarkably improved electrocatalytic activity in the oxygen reduction reaction in both alkaline and acidic media. Ab initio molecular dynamic simulations indicated that rapid H transfer and the thermodynamic stability of six-membered N structures promoted the transformation of N-containing species from pyrrolic to pyridinic at 600 ℃ In O2-staturated 0.1 M KOH solution, the half-wave potential （El/2） of NG-A was only 62 mV lower than that of a commercial Pt/C catalyst, and the limiting current density of NG-A was 0.5 mA.cm-2 larger than that of Pt/C. Koutecky-Levich （K-L） plots and rotating ring-disk electrode measurement indicated a four-electron- transfer pathway in NG-A, which could be ascribed to its high content of pyridinic N.
文摘Understanding how small molecules interface with amyloid fibrils at the nanoscale is of importance for developing therapeutic treatments against amyloid-based diseases. Here, we show for the first time that human islet amyloid polypeptides （LAPP） in the fibrillar form are polymorphic, ambidextrous, and possess multiple periodicities. Upon interfacing with the small molecule epigallocatechin gallate （EGCG）, IAPP aggregation was rendered off-pathway and assumed a form with soft and disordered clusters, while mature IAPP fibrils displayed kinks and branching but conserved the twisted fibril morphology. These nanoscale phenomena resulted from competitive interactions between EGCG and the IAPP amyloidogenic region, as well as end capping of the fibrils by the small molecule. This information is crucial in delineating IAPP toxicity implicated in type 2 diabetes and for developing new inhibitors against amyloidogenesis.
