562 research outputs found
Anisotropic coarse-grained statistical potentials improve the ability to identify native-like protein structures
We present a new method to extract distance and orientation dependent
potentials between amino acid side chains using a database of protein
structures and the standard Boltzmann device. The importance of orientation
dependent interactions is first established by computing orientational order
parameters for proteins with alpha-helical and beta-sheet architecture.
Extraction of the anisotropic interactions requires defining local reference
frames for each amino acid that uniquely determine the coordinates of the
neighboring residues. Using the local reference frames and histograms of the
radial and angular correlation functions for a standard set of non-homologue
protein structures, we construct the anisotropic pair potentials. The
performance of the orientation dependent potentials was studied using a large
database of decoy proteins. The results demonstrate that the new distance and
orientation dependent residue-residue potentials present a significantly
improved ability to recognize native folds from a set of native and decoy
protein structures.Comment: Submitted to "The Journal of Chemical Physics
Insights into the structure and dynamics of lysyl oxidase propeptide, a flexible protein with numerous partners
Lysyl oxidase (LOX) catalyzes the oxidative deamination of lysine and hydroxylysine residues in collagens and elastin, which is the first step of the cross-linking of these extracellular matrix proteins. It is secreted as a proenzyme activated by bone morphogenetic protein-1, which releases the LOX catalytic domain and its bioactive N-terminal propeptide. We characterized the recombinant human propeptide by circular dichroism, dynamic light scattering, and small-angle X-ray scattering (SAXS), and showed that it is elongated, monomeric, disordered and flexible (Dmax: 11.7 nm, Rg: 3.7 nm). We generated 3D models of the propeptide by coarse-grained molecular dynamics simulations restrained by SAXS data, which were used for docking experiments. Furthermore, we have identified 17 new binding partners of the propeptide by label-free assays. They include four glycosaminoglycans (hyaluronan, chondroitin, dermatan and heparan sulfate), collagen I, cross-linking and proteolytic enzymes (lysyl oxidase-like 2, transglutaminase-2, matrix metalloproteinase-2), a proteoglycan (fibromodulin), one growth factor (Epidermal Growth Factor, EGF), and one membrane protein (tumor endothelial marker-8). This suggests new roles for the propeptide in EGF signaling pathway
Mechanism of fiber assembly: Treatment of Aβ peptide aggregation with a coarse-grained united-residue force field
The growth mechanism of β-amyloid (Aβ) peptide fibrils was studied by a physics-based coarse-grained united-residue model and molecular dynamics (MD) simulations. To identify the mechanism of monomer addition to an Aβ1-40 fibril, we placed an unstructured monomer at a distance of 20 Å from a fibril template and allowed it to interact freely with the latter. The monomer was not biased towards fibril conformation by either the force field or the MD algorithm. With the use of a coarse-grained model with replica-exchange molecular dynamics, a longer timescale was accessible, making it possible to observe how the monomers probe different binding modes during their search for the fibril conformation. Although different assembly pathways were seen, they all follow a dock-lock mechanism with two distinct locking stages, consistent with experimental data on fibril elongation. Whereas these experiments have not been able to characterize the conformations populating the different stages, we have been able to describe these different stages explicitly by following free monomers as they dock onto a fibril template and to adopt the fibril conformation (i.e., we describe fibril elongation step by step at the molecular level). During the first stage of the assembly ( docking ), the monomer tries different conformations. After docking, the monomer is locked into the fibril through two different locking stages. In the first stage, the monomer forms hydrogen bonds with the fibril template along one of the strands in a two-stranded β-hairpin; in the second stage, hydrogen bonds are formed along the second strand, locking the monomer into the fibril structure. The data reveal a free-energy barrier separating the two locking stages. The importance of hydrophobic interactions and hydrogen bonds in the stability of the Aβ fibril structure was examined by carrying out additional canonical MD simulations of oligomers with different numbers of chains (4-16 chains), with the fibril structure as the initial conformation. The data confirm that the structures are stabilized largely by hydrophobic interactions and show that intermolecular hydrogen bonds are highly stable and contribute to the stability of the oligomers as well. © 2010 Elsevier Ltd
Unfolding the prospects of computational (bio)materials modelling
In this perspective communication, we briefly sketch the current state of computational (bio)material research and discuss possible solutions for the four challenges that have been increasingly identified within this community: (i) the desire to develop a unified framework for testing the consistency of implementation and physical accuracy for newly developed methodologies, (ii) the selection of a standard format that can deal with the diversity of simulation data and at the same time simplifies data storage, data exchange, and data reproduction, (iii) how to deal with the generation, storage, and analysis of massive data, and (iv) the benefits of efficient 'core' engines. Expressed viewpoints are the result of discussions between computational stakeholders during a Lorentz center workshop with the prosaic title Workshop on Multi-scale Modeling and are aimed at (i) improving validation, reporting and reproducibility of computational results, (ii) improving data migration between simulation packages and with analysis tools, (iii) popularizing the use of coarse-grained and multi-scale computational tools among non-experts and opening up these modern computational developments to an extended user community
Geometrical model for the native-state folds of proteins
We recently introduced a physical model [Hoang et al., P. Natl. Acad. Sci.
USA (2004), Banavar et al., Phys. Rev. E (2004)] for proteins which
incorporates, in an approximate manner, several key features such as the
inherent anisotropy of a chain molecule, the geometrical and energetic
constraints placed by the hydrogen bonds and sterics, and the role played by
hydrophobicity. Within this framework, marginally compact conformations
resembling the native state folds of proteins emerge as broad competing minima
in the free energy landscape even for a homopolymer. Here we show how the
introduction of sequence heterogeneity using a simple scheme of just two types
of amino acids, hydrophobic (H) and polar (P), and sequence design allows a
selected putative native fold to become the free energy minimum at low
temperature. The folding transition exhibits thermodynamic cooperativity, if
one neglects the degeneracy between two different low energy conformations
sharing the same fold topology.Comment: 12 pages, 3 figure
Improvements and new functionalities of UNRES server for coarse-grained modeling of protein structure, dynamics, and interactions
In this paper we report the improvements and extensions of the UNRES server (https://unres-server.chem.ug.edu.pl) for physics-based simulations with the coarse-grained UNRES model of polypeptide chains. The improvements include the replacement of the old code with the recently optimized one and adding the recent scale-consistent variant of the UNRES force field, which performs better in the modeling of proteins with the β and the α+β structures. The scope of applications of the package was extended to data-assisted simulations with restraints from nuclear magnetic resonance (NMR) and chemical crosslink mass-spectroscopy (XL-MS) measurements. NMR restraints can be input in the NMR Exchange Format (NEF), which has become a standard. Ambiguous NMR restraints are handled without expert intervention owing to a specially designed penalty function. The server can be used to run smaller jobs directly or to prepare input data to run larger production jobs by using standalone installations of UNRES
Protein-Ligand Interaction Energy-Based Entropy Calculations: Fundamental Challenges For Flexible Systems
Entropy calculations represent one of the most challenging steps in obtaining the
binding free energy in biomolecular systems. A novel computationally effective approach (IE)
was recently proposed to calculate the entropy based on the computation of protein-ligand
interaction energy directly from molecular dynamics (MD) simulations. We present a study
focused on the application of this method to flexible molecular systems and compare its
performance with well-established normal mode (NM) and quasiharmonic (QH) entropy
calculation approaches. Our results raise substantial concerns on the general applicability of IE in
terms of reproducibility, reasonable absolute values of the entropy and agreement with NM and
QM approaches. IE shows significant variation in the computed entropy values depending on the
MD frames chosen for calculations. These deviations render reproducibility of IE calculations to
be far from sufficient. We conclude that IE is recommended to be used after substantial modifications with respect to its sampling methodology
Ab initio theory of helix-coil phase transition
In this paper we suggest a theoretical method based on the statistical
mechanics for treating the alpha-helix-random coil transition in alanine
polypeptides. We consider this process as a first-order phase transition and
develop a theory which is free of model parameters and is based solely on
fundamental physical principles. It describes essential thermodynamical
properties of the system such as heat capacity, the phase transition
temperature and others from the analysis of the polypeptide potential energy
surface calculated as a function of two dihedral angles, responsible for the
polypeptide twisting. The suggested theory is general and with some
modification can be applied for the description of phase transitions in other
complex molecular systems (e.g. proteins, DNA, nanotubes, atomic clusters,
fullerenes).Comment: 24 pages, 3 figure
- …