Mai Suan Li

Institute of Physics of the Polish Academy of Sciences, Warszawa, Masovian Voivodeship, Poland

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Publications (121)345.46 Total impact

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    ABSTRACT: Fibril formation resulting from protein misfolding and aggregation is a hallmark of several neurodegenerative diseases such as Alzheimer’s and Parkinson’s diseases. Despite the fact that the fibril formation process is very slow and thus poses a significant challenge for theoretical and experimental studies, a number of alternative pictures of molecular mechanisms of amyloid fibril formation have been recently proposed. What seems to be common for the majority of the proposed models is that fibril elongation involves the formation of pre-nucleus seeds prior to the creation of a critical nucleus. Once the size of the pre-nucleus seed reaches the critical nucleus, its thermal fluctuations are expected to be small and the resulting nucleus provides a template for sequential (one-by-one) accommodation of added monomers. The effect of template fluctuations on fibril formation rates has not been explored either experimentally or theoretically so far. In this paper we make the first attempt at solving this problem by two sets of simulations. To mimic small template fluctuations, in one set, monomers of the preformed template are kept fixed, while in the other set they are allowed to fluctuate. The kinetics of addition of a new peptide onto the template is explored using all-atom simulations with explicit water and the GROMOS96 43a1 force field and simple lattice models. Our result demonstrates that preformed template fluctuations can modulate protein aggregation rates and pathways. The association of a nascent monomer with the template obeys the kinetics partitioning mechanism where the intermediate state occurs in a fraction of routes to the protofibril. It was shown that template immobility greatly increases the time of incorporating a new peptide into the preformed template compared to the fluctuating template case. This observation has also been confirmed by simulation using lattice models and may be invoked to understand the role of template fluctuations in slowing down fibril elongation in vivo.
    The Journal of Chemical Physics 04/2015; DOI:10.1063/1.4917073 · 3.12 Impact Factor
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    Dataset: tq318b-c
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    ABSTRACT: Self-assembly of Aβ peptides into amyloid aggregates has been suggested as the major cause of Alzheimer's disease (AD). Nowadays, there is no medication for AD, but experimental data indicate that reversion of the process of amyloid aggregation reduces the symptoms of disease. In this paper all 8000 tripeptides were studied for their ability to destroy Aβ fibrils. The docking method and the more sophisticated MM-PBSA (molecular mechanics Poisson-Boltzmann surface area) method were employed to calculate the binding affinity and mode of tripeptides to Aβ fibrils. The ability of these peptides to depolymerize Aβ fibrils was also investigated experimentally using atomic force microscopy and fluorescence spectroscopy (Thioflavin T assay). It was shown that tripeptides prefer to bind to hydrophobic regions of 6Aβ9-40 fibrils. Tripeptides WWW, WWP, WPW and PWW were found to be the most potent binders. In vitro experiments showed that tight-binding tripeptides have significant depolymerizing activities and their DC50 values determined from dose-response curves were in micromolar range. The ability of non-binding (GAM, AAM) and weak-binding (IVL and VLA) tripeptides to destroy Aβ fibrils was negligible. In vitro data of tripeptide depolymerizing activities support the predictions obtained by molecular docking and all-atom simulation methods. Our results suggest that presence of multiple complexes of heterocycles forming by Tryptophan and Proline residues in tripeptides is crucial for their tight binding to Aβ fibrils as well as for extensive fibril depolymerization. We recommend PWW for further studies as it has the lowest experimental binding constant.
    The Journal of Physical Chemistry B 03/2015; DOI:10.1021/acs.jpcb.5b00006 · 3.38 Impact Factor
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    ABSTRACT: The formation of insulin amyloid fibrils leads to accumulation of protein aggregates at the sites of insulin injection and interferes with insulin delivery for treatment of diabetes. We investigated the ability of small molecules, aromatic glyco-acridine derivatives, to prevent insulin fibrillization. The fluorescence spectroscopy and atomic force microscopy shown that glyco-acridines interfere with insulin aggregation and that their inhibitory activity depends on their structure. The binding free energies, estimated by all-atom molecular dynamics simulations, indicate that non-polar interaction is the key factor controlling the binding affinity of glyco-acridine derivatives to insulin. We introduced, for the first time, geometrical descriptors that allowed us to distinguish the binding affinities of stereo-isomers. The binding free energies correlate with the distance between planes of the acridine tricyclic core and side parts in unbound and bound states. In addition the aromatic part of glyco-acridines is important for directing the ligand - dimer insulin interaction. Our findings may provide a basis for the development of new small molecule inhibitors for therapy of amyloid-related diseases.
    Medicinal Chemistry Communication 02/2015; DOI:10.1039/C5MD00004A · 2.63 Impact Factor
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    ABSTRACT: The binding mechanism of AC1NX476 to HIV-1 protease wild-type and mutations was studied by the docking and molecular dynamics simulations. The binding free energy was calculated using the double-annihilation binding-free energy method. It is shown that the binding affinity of AC1NX476 to wild-type is higher than not only ritonavir but also darunavir making AC1NX476 become attractive candidate for HIV treatment. Our theoretical results are in excellent agreement with the experiment data as the correlation coefficient between calculated and experimentally measured binding free energies. Residues Asp25-A, Asp29-A, Asp30-A, Ile47-A, Gly48-A, and Val50-A from chain A, and Asp25-B from chain B play a crucial role in the ligand binding. The mutations were found to reduce the receptor-ligand interaction by widening the binding cavity and the binding propensity is mainly driven by the van der Waals interaction. Our finding may be useful for designing potential drugs to combat with HIV.This article is protected by copyright. All rights reserved.
    Chemical Biology &amp Drug Design 01/2015; DOI:10.1111/cbdd.12518 · 2.51 Impact Factor
  • Pham Dinh Quoc Huy, Mai Suan Li
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    ABSTRACT: Binding affinity of fullerenes C20, C36, C60, C70 and C84 for amyloid beta fibrils is studied by docking and all-atom molecular dynamics simulations with the Amber force field and water model TIP3P. Using the molecular mechanic-Poisson Boltzmann surface area method one can demonstrate that the binding free energy linearly decreases with the number of carbon atoms of fullerene, i.e. the larger is the fullerene size, the higher is the binding affinity. Overall, fullerenes bind to Aβ9-40 fibrils stronger than to Aβ17-42. The number of water molecules trapped in the interior of 12Aβ9-40 fibrils was found to be lower than inside pentamer 5Aβ17-42. C60 destroys Aβ17-42 fibril structure to a greater extent compared to other fullerenes. Our study revealed that the van der Waals interaction dominates over the electrostatic interaction and non-polar residues of amyloid beta peptides play the significant role in interaction with fullerenes providing novel insight into the development of drug candidates against Alzheimer's disease.
    Physical Chemistry Chemical Physics 08/2014; 16(37). DOI:10.1039/c4cp02348j · 4.20 Impact Factor
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    ABSTRACT: Recent experiments have shown that the Taiwan mutation (D7H) slows down the fibril formation of amyloid peptides Abeta40 and Abeta42. Motivated by this finding we have studied the influence of D7H mutation on structures of Abeta peptide monomers using the replica exchange molecular dynamics simulations with OPLS force field and implicit water model. Our study reveals that the mechanism behind modulation of aggregation rates is associated with decrease of beta-content and dynamics of the salt bridge D23-K28. Estimating the bending free energy of this salt bridge we have found that, in agreement with the experiments, the fibril formation rate of both peptides Abeta40 and Abeta42 is reduced about two times by mutation.
    The Journal of Physical Chemistry B 07/2014; 118(30). DOI:10.1021/jp503652s · 3.38 Impact Factor
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    ABSTRACT: The self-assembly of the amyloid beta (Abeta) peptides into senile plaques is the hallmark of Alzheimer's disease. Recent experiments have shown that the English familial disease mutation (H6R) speeds up the fibril formation process of alloforms Abeta40 and Abeta42 peptides altering their toxicity to cells. We used all-atom molecular dynamics simulations at microsecond-time scales with the OPLS-AA force field and TIP3P explicit water model to study the structural dynamics of the monomer and dimer of H6R sequences of both peptides. The reason behind the self-assembly acceleration is common that upon mutation the net charge is reduced leading to the weaker repulsive interaction between chains that facilitates the peptide association. However, we can show that the acceleration mechanisms are different for different peptides: the rate of fibril formation of Abeta42 increases due to the increase of beta-structure at the C-terminal in both monomer and dimer, while the enhancement of stability of the salt bridge Asp23-Lys28 plays the key role for Abeta40. Overall, our study provides a detailed atomistic picture of the H6R-mediated conformational changes that are consistent with the experimental findings and highlights the important role of the N-terminal in Abeta peptide aggregation.
    ACS Chemical Neuroscience 06/2014; 5(8). DOI:10.1021/cn500007j · 4.21 Impact Factor
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    ABSTRACT: Stationary Josephson currentIc in symmetric and non-symmetric junctions involving d-wave superconductors with charge density waves (CDWs) was calculated. It was found that, if CDWs are weak or absent, there exists an approximate proportionality betweenIc and the product of superconducting order parameters in the electrodes (the lawof corresponding states) for several factors affecting those quantities, such as the temperature,T, or one of the parameters characterizing the combined CDW superconducting phase (the degree of the Fermi surface dielectric gapping and the ratio between the parent superconducting and CDW order parameters). Otherwise, the dependencesIc(T) were shown to deviate from those in the absence of CDWs, and the relevant corresponding-state dependences from linearity, the deviations being especially strong at certain rotation angles of crystalline electodes with respect to the junction plane. Hence, making use of specially designed experimental setups and analyzing theIc(T) and correspondingstate dependences, the existence of CDWs in cuprates and other non-conventional superconductors can be detected.
    The European Physical Journal B 05/2014; 87(5):115. DOI:10.1140/epjb/e2014-41063-0 · 1.46 Impact Factor
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    ABSTRACT: Amyloid oligomers and plaques are composed of multiple chemically identical proteins. Therefore, one of the first fundamental problems in the characterization of structures from simulations is the treatment of the degeneracy, i.e., the permutation of the molecules. Second, the intramolecular and intermolecular degrees of freedom of the various molecules must be taken into account. Currently, the well-known dihedral principal component analysis method only considers the intramolecular degrees of freedom, and other methods employing collective variables can only describe intermolecular degrees of freedom at the global level. With this in mind, we propose a general method that identifies all the structures accurately. The basis idea is that the intramolecular and intermolecular states are described in terms of combinations of single-molecule and double-molecule states, respectively, and the overall structures of oligomers are the product basis of the intramolecular and intermolecular states. This way, the degeneracy is automatically avoided. The method is illustrated on the conformational ensemble of the tetramer of the Alzheimer's peptide Aβ9-40, resulting from two atomistic molecular dynamics simulations in explicit solvent, each of 200 ns, starting from two distinct structures.
    The Journal of Chemical Physics 03/2014; 140(9):094105. DOI:10.1063/1.4866902 · 3.12 Impact Factor
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    ABSTRACT: The influence of water models SPC, SPC/E, TIP3P, and TIP4P on ligand binding affinity is examined by calculating the binding free energy ΔGbind of oseltamivir carboxylate (Tamiflu) to the wild type of glycoprotein neuraminidase from the pandemic A/H5N1 virus. ΔGbind is estimated by the Molecular Mechanic-Poisson Boltzmann Surface Area method and all-atom simulations with different combinations of these aqueous models and four force fields AMBER99SB, CHARMM27, GROMOS96 43a1, and OPLS-AA/L. It is shown that there is no correlation between the binding free energy and the water density in the binding pocket in CHARMM. However, for three remaining force fields ΔGbind decays with increase of water density. SPC/E provides the lowest binding free energy for any force field, while the water effect is the most pronounced in CHARMM. In agreement with the popular GROMACS recommendation, the binding score obtained by combinations of AMBER-TIP3P, OPLS-TIP4P, and GROMOS-SPC is the most relevant to the experiments. For wild-type neuraminidase we have found that SPC is more suitable for CHARMM than TIP3P recommended by GROMACS for studying ligand binding. However, our study for three of its mutants reveals that TIP3P is presumably the best choice for CHARMM.
    The Scientific World Journal 02/2014; 2014:536084. DOI:10.1155/2014/536084 · 1.73 Impact Factor
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    ABSTRACT: Fibril formation of proteins and peptides is associated with a large group of major human diseases, including Alzheimer’s disease, prion disorders, amyotrophic lateral sclerosis, type 2 diabetes, etc. Therefore, understanding the key factors that govern this process is of paramount importance. The fibrillogenesis of polypeptide chains depends on their intrinsic properties as well as on the external conditions. In this mini-review we discuss the relationship between fibril formation kinetics and the sequence, aromaticity, hydrophobicity, charge and population of the so called fibril-prone conformation in a monomer state. The higher the population, the faster is the fibril elongation and this dependence may be described by a single exponential function. This observation opens up a new way to understand the fibrillogenesis of bio-molecules at the monomer level. We will also discuss the influence of the environment with focus on the recently observed dual effect of crowders on the aggregation rates of polypeptide chains.
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    ABSTRACT: By the virtual screening method we have screened out Dihydrochalcone as a top-lead for the Alzheimer's disease using the database of about 32364 natural compounds. The binding affinity of this ligand to amyloid beta (A[Formula: see text]) fibril has been thoroughly studied by computer simulation and experiment. Using the Thioflavin T (ThT) assay we have obtained the inhibition constant IC50 [Formula: see text]M. This result is in good agreement with the estimation of the binding free energy obtained by the molecular mechanic-Poisson Boltzmann surface area method and all-atom simulation with the force field CHARMM 27 and water model TIP3P. Cell viability assays indicated that Dihydrochalcone could effectively reduce the cytotoxicity induced by A[Formula: see text]. Thus, both in silico and in vitro studies show that Dihydrochalcone is a potential drug for the Alzheimers disease.
    PLoS ONE 11/2013; 8(11):e79151. DOI:10.1371/journal.pone.0079151 · 3.53 Impact Factor
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    ABSTRACT: Recent experiments have shown that the mutation Tottori (D7N) alters the toxicity, assembly and rate of fibril formation of the wild type (WT) amyloid beta (Aβ) Aβ40 and Aβ42 peptides. We used all-atom molecular dynamics simulations in explicit solvent of the monomer and dimer of both alloforms with their WT and D7N sequences. The monomer simulations starting from a random coil and totaling 3 μs show that the D7N mutation changes the fold and the network of salt bridges in both alloforms. The dimer simulations starting from the amyloid fibrillar states and totaling 4.4 μs also reveal noticeable changes in terms of secondary structure, salt bridge, and topology. Overall, this study provides physical insights into the enhanced rate of fibril formation upon D7N mutation and an atomic picture of the D7N-mediated conformational change on Aβ40 and Aβ42 peptides.
    ACS Chemical Neuroscience 09/2013; DOI:10.1021/cn400110d · 4.21 Impact Factor
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    Dataset: jcp supp
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    Dataset: jcp supp
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    ABSTRACT: We discuss the use of a structure based Cα-Go model and Langevin dynamics to study in detail the mechanical properties and unfolding pathway of the titin I27 domain. We show that a simple Go-model does detect correctly the origin of the mechanical stability of this domain. The unfolding free energy landscape parameters xu and ΔG(‡), extracted from dependencies of unfolding forces on pulling speeds, are found to agree reasonably well with experiments. We predict that above v = 10(4) nm/s the additional force-induced intermediate state is populated at an end-to-end extension of about 75 A. The force-induced switch in the unfolding pathway occurs at the critical pulling speed vcrit ≈ 10(6)-10(7) nm/s. We argue that this critical pulling speed is an upper limit of the interval where Bell's theory works. However, our results suggest that the Go-model fails to reproduce the experimentally observed mechanical unfolding pathway properly, yielding an incomplete picture of the free energy landscape. Surprisingly, the experimentally observed intermediate state with the A strand detached is not populated in Go-model simulations over a wide range of pulling speeds. The discrepancy between simulation and experiment is clearly seen from the early stage of the unfolding process which shows the limitation of the Go model in reproducing unfolding pathways and deciphering the complete picture of the free energy landscape.
    The Journal of Chemical Physics 08/2013; 139(6):065103. DOI:10.1063/1.4817773 · 3.12 Impact Factor
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    ABSTRACT: The tunnel conductance G(V) for break junctions made of single-crystal as-grown Bi2Sr2CaCu2O8+δ samples with Tc≈86–89 K were measured and clear-cut dip-hump structures (DHSs) were found in the range 80–120 mV of the bias voltage V. A theory of tunneling in symmetrical junctions between inhomogeneous charge-density-wave (CDW) superconductors, considered in the framework of the s-pairing model, has been developed. CDWs have been shown to be responsible for the appearance of the DHS in the tunnel current-voltage characteristics and properly describe the experimental results.
    Physical Review B 06/2013; 76(18). DOI:10.1103/PhysRevB.76.180503 · 3.66 Impact Factor
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Publication Stats

2k Citations
345.46 Total Impact Points

Institutions

  • 2015
    • Institute of Physics of the Polish Academy of Sciences
      Warszawa, Masovian Voivodeship, Poland
  • 2014
    • Institut Universitaire de France
      Lutetia Parisorum, Île-de-France, France
  • 1990–2014
    • Polish Academy of Sciences
      • Institute of Physics
      Warszawa, Masovian Voivodeship, Poland
  • 2009–2012
    • Academia Sinica
      • Institute of Physics
      T’ai-pei, Taipei, Taiwan