Mai Suan Li

Monomer adds to preformed structured oligomers of Aβ-peptides by a two-stage dock–lock mechanism

Nonfibrillar soluble oligomers, which are intermediates in the transition from monomers to amyloid fibrils, may be the toxic species in Alzheimers disease. To monitor the early events that direct assembly of amyloidogenic peptides we probe the dynamics of formation of (Aβ16–22)n by adding a monomer to a preformed (Aβ16–22)n−1 (n = 4–6) oligomer in which the peptides are arranged in an antiparallel β-sheet conformation. All atom molecular dynamics simulations in water and multiple long trajectories, for a cumulative time of 6.9 μs, show that the oligomer grows by a two-stage dock–lock mechanism. The largest conformational change in the added disordered monomer occurs during the rapid (≈50 ns) first dock stage in which the β-strand content of the monomer increases substantially from a low initial value. In the second slow-lock phase, the monomer rearranges to form in register antiparallel structures. Surprisingly, the mobile structured oligomers undergo large conformational changes in order to accommodate the added monomer. The time needed to incorporate the monomer into the fluid-like oligomer grows even when n = 6, which suggests that the critical nucleus size must exceed six. Stable antiparallel structure formation exceeds hundreds of nanoseconds even though frequent interpeptide collisions occur at elevated monomer concentrations used in the simulations. The dock–lock mechanism should be a generic mechanism for growth of oligomers of amyloidogenic peptides.

Amyloid β Protein and Alzheimer’s Disease: When Computer Simulations Complement Experimental Studies

Simulations Complement Experimental Studies Jessica Nasica-Labouze,† Phuong H. Nguyen,† Fabio Sterpone,† Olivia Berthoumieu,‡ Nicolae-Viorel Buchete, Sebastien Cote, Alfonso De Simone, Andrew J. Doig, Peter Faller,‡ Angel Garcia, Alessandro Laio, Mai Suan Li, Simone Melchionna, Normand Mousseau, Yuguang Mu, Anant Paravastu, Samuela Pasquali,† David J. Rosenman, Birgit Strodel, Bogdan Tarus,† John H. Viles, Tong Zhang,†,▲ Chunyu Wang, and Philippe Derreumaux*,†,□ †Laboratoire de Biochimie Theorique, Institut de Biologie Physico-Chimique (IBPC), UPR9080 CNRS, Universite Paris Diderot, Sorbonne Paris Cite, 13 rue Pierre et Marie Curie, 75005 Paris, France ‡LCC (Laboratoire de Chimie de Coordination), CNRS, Universite de Toulouse, Universite Paul Sabatier (UPS), Institut National Polytechnique de Toulouse (INPT), 205 route de Narbonne, BP 44099, Toulouse F-31077 Cedex 4, France School of Physics & Complex and Adaptive Systems Laboratory, University College Dublin, Belfield, Dublin 4, Ireland Deṕartement de Physique and Groupe de recherche sur les proteines membranaires (GEPROM), Universite de Montreal, C.P. 6128, succursale Centre-ville, Montreal, Quebec H3C 3T5, Canada Department of Life Sciences, Imperial College London, London SW7 2AZ, United Kingdom Manchester Institute of Biotechnology, University of Manchester, 131 Princess Street, Manchester M1 7DN, United Kingdom Department of Physics, Applied Physics, & Astronomy, and Department of Biology, Rensselaer Polytechnic Institute, Troy, New York 12180, United States The International School for Advanced Studies (SISSA), Via Bonomea 265, 34136 Trieste, Italy Institute of Physics, Polish Academy of Sciences, Al. Lotnikow 32/46, 02-668 Warsaw, Poland Institute for Computational Science and Technology, SBI Building, Quang Trung Software City, Tan Chanh Hiep Ward, District 12, Ho Chi Minh City, Vietnam Instituto Processi Chimico-Fisici, CNR-IPCF, Consiglio Nazionale delle Ricerche, 00185 Roma, Italy School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, 637551 Singapore Department of Chemical and Biomedical Engineering, Florida A&M University-Florida State University (FAMU-FSU) College of Engineering, 2525 Pottsdamer Street, Tallahassee, Florida 32310, United States National High Magnetic Field Laboratory, 1800 East Paul Dirac Drive, Tallahassee, Florida 32310, United States Institute of Complex Systems: Structural Biochemistry (ICS-6), Forschungszentrum Julich GmbH, 52425 Julich, Germany School of Biological and Chemical Sciences, Queen Mary University of London, London E1 4NS, United Kingdom Institut Universitaire de France, 75005 Paris, France

Free energy landscape and folding mechanism of a β‐hairpin in explicit water: A replica exchange molecular dynamics study

The free energy landscape and the folding mechanism of the C‐terminal β‐hairpin of protein G is studied by extensive replica exchange molecular dynamics simulations (40 replicas and 340 ns total simulation time), using the GROMOS96 force field and the SPC explicit water solvent. The study reveals that the system preferentially adopts a β‐hairpin structure at biologically important temperatures, and that the helix content is low at all temperatures studied. Representing the free energy landscape as a function of several types of reaction coordinates, four local minima corresponding to the folded, partially folded, molten globule, and unfolded states are identified. The findings suggest that the folding of the β‐hairpin occurs as the sequence: collapse of hydrophobic core → formation of H‐bond → formation of the turn. Identifying the folded and molten globule states as the main conformations, the free energy landscape of the β‐hairpin is consistent with a two‐state behavior with a broad transition state. The temperature dependence of the folding–unfolding transition is investigated in some detail. The enthalpy and entropy jumps at the folding transition temperature are found to be about three times lower than the experimental estimates, indicating that the folding–unfolding transition in silico is less cooperative than its in vitro counterpart. Proteins 2005.

Inhibition of Aggregation of Amyloid Peptides by Beta-Sheet Breaker Peptides and Their Binding Affinity

The effects of beta-sheet breaker peptides KLVFF and LPFFD on the oligomerization of amyloid peptides were studied by all-atom simulations. It was found that LPFFD interferes the aggregation of Aβ(16-22) peptides to a greater extent than does KLVFF. Using the molecular mechanics-Poisson-Boltzmann surface area (MM-PBSA) method, we found that the former binds more strongly to Aβ(16-22). Therefore, by simulations, we have clarified the relationship between aggregation rates and binding affinity: the stronger the ligand binding, the slower the oligomerization process. The binding affinity of pentapeptides to full-length peptide Aβ(1-40) and its mature fibrils has been considered using the Autodock and MM-PBSA methods. The hydrophobic interaction between ligands and receptors plays a more important role for association than does hydrogen bonding. The influence of beta-sheet breaker peptides on the secondary structures of monomer Aβ(1-40) was studied in detail, and it turns out that, in their presence, the total beta-sheet content can be enhanced. However, the aggregation can be slowed because the beta-content is reduced in fibril-prone regions. Both pentapeptides strongly bind to monomer Aβ(1-40), as well as to mature fibrils, but KLVFF displays a lower binding affinity than LPFFD. Our findings are in accord with earlier experiments that both of these peptides can serve as prominent inhibitors. In addition, we predict that LPFFD inhibits/degrades the fibrillogenesis of full-length amyloid peptides better than KLVFF. This is probably related to a difference in their total hydrophobicities in that the higher the hydrophobicity, the lower the inhibitory capacity. The GROMOS96 43a1 force field with explicit water and the force field proposed by Morris et al. (Morris et al. J. Comput. Chem. 1998, 19, 1639 ) were employed for all-atom molecular dynamics simulations and Autodock experiments, respectively.

Scaling of Folding Properties in Simple Models of Proteins

Scaling of folding properties of proteins is studied in a toy system — the lattice Go model with various two- and three-dimensional geometries of the maximally compact native states. Characteristic folding times grow as power laws with the system size. The corresponding exponents are not universal. Scaling of the thermodynamic stability also indicates size-related deterioration of the folding properties.

Effect of the Tottori Familial Disease Mutation (D7N) on the Monomers and Dimers of Aβ40 and Aβ42

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.

Top leads for swine influenza A/H1N1 virus revealed by steered molecular dynamics approach.

Since March 2009, the rapid spread of infection during the recent A/H1N1 swine flu pandemic has raised concerns of a far more dangerous outcome should this virus become resistant to current drug therapies. Currently oseltamivir (tamiflu) is intensively used for the treatment of influenza and is reported effective for 2009 A/H1N1 virus. However, as this virus is evolving fast, some drug-resistant strains are emerging. Therefore, it is critical to seek alternative treatments and identify roots of the drug resistance. In this paper, we use the steered molecular dynamics (SMD) approach to estimate the binding affinity of ligands to the glycoprotein neuraminidase. Our idea is based on the hypothesis that the larger is the force needed to unbind a ligand from a receptor the higher its binding affinity. Using all-atom models with Gromos force field 43a1 and explicit water, we have studied the binding ability of 32 ligands to glycoprotein neuraminidase from swine flu virus A/H1N1. The electrostatic interaction is shown to play a more important role in binding affinity than the van der Waals one. We have found that four ligands 141562, 5069, 46080, and 117079 from the NSC set are the most promising candidates to cope with this virus, while peramivir, oseltamivir, and zanamivir are ranked 8, 11, and 20. The observation that these four ligands are better than existing commercial drugs has been also confirmed by our results on the binding free energies obtained by the molecular mechanics-Poisson-Boltzmann surface area (MM-PBSA) method. Our prediction may be useful for the therapeutic application.

Curcumin Binds to Aβ1–40 Peptides and Fibrils Stronger Than Ibuprofen and Naproxen

Binding of curcumin, naproxen, and ibuprofen to Aβ1-40 peptide and its fibrils is studied by docking method and all-atom molecular dynamics simulations. The Gromos96 43a1 force field and simple point charge model of water have been used for molecular dynamics simulations. It is shown that if the receptor is a monomer then naproxen and ibuprofen are bound to the same place that is different from the binding position of curcumin. However all of three ligands have the same binding pocket in fibrillar structures. The binding mechanism is studied in detail showing that the van der Waals interaction between ligand and receptor dominates over the electrostatic interaction. The binding free energies obtained by the molecular mechanic-Poisson-Boltzmann surface area method indicate that curcumin displays higher binding affinity than nonsteroidal anti-inflammatory drugs. Our results are in good agreement with the experiments.

Refolding upon Force Quench and Pathways of Mechanical and Thermal Unfolding of Ubiquitin

The refolding from stretched initial conformations of ubiquitin (PDB ID: 1ubq) under the quenched force is studied using the C(alpha)-Gō model and the Langevin dynamics. It is shown that the refolding decouples the collapse and folding kinetics. The force-quench refolding-times scale as tau(F) approximately exp(f(q)Deltax(F)/k(B)T), where f(q) is the quench force and Deltax(F) approximately 0.96 nm is the location of the average transition state along the reaction coordinate given by the end-to-end distance. This value is close to Deltax(F) approximately 0.8 nm obtained from the force-clamp experiments. The mechanical and thermal unfolding pathways are studied and compared with the experimental and all-atom simulation results in detail. The sequencing of thermal unfolding was found to be markedly different from the mechanical one. It is found that fixing the N-terminus of ubiquitin changes its mechanical unfolding pathways much more drastically compared to the case when the C-end is anchored. We obtained the distance between the native state and the transition state Deltax(UF) approximately 0.24 nm, which is in reasonable agreement with the experimental data.

Neuraminidase inhibitor R-125489 - A promising drug for treating influenza virus: Steered molecular dynamics approach

Two neuraminidase inhibitors, oseltamivir and zanamivir, are important drug treatments for influenza. Oseltamivir-resistant mutants of the influenza virus A/H1N1 and A/H5N1 have emerged, necessitating the development of new long-acting antiviral agents. One such agent is a new neuraminidase inhibitor R-125489 and its prodrug CS-8958. An atomic level understanding of the nature of this antiviral agents binding is still missing. We address this gap in our knowledge by applying steered molecular dynamics (SMD) simulations to different subtypes of seasonal and highly pathogenic influenza viruses. We show that, in agreement with experiments, R-125489 binds to neuraminidase more tightly than CS-8958. Based on results obtained by SMD and the molecular mechanics-Poisson-Boltzmann surface area method, we predict that R-125489 can be used to treat not only wild-type but also tamiflu-resistant N294S, H274Y variants of A/H5N1 virus as its binding affinity does not vary much across these systems. The high correlation level between theoretically determined rupture forces and experimental data on binding energies for the large number of systems studied here implies that SMD is a promising tool for drug design.