A critical step of β-amyloid fibril formation is fibril elongation in which amyloid-β monomers undergo structural transitions to fibrillar structures upon their binding to fibril tips. The atomic ...detail of the structural transitions remains poorly understood. Computational characterization of the structural transitions is limited so far to short Aβ segments (5–10 aa) owing to the long time scale of Aβ fibril elongation. To overcome the computational time scale limit, we combined a hybrid-resolution model with umbrella sampling and replica exchange molecular dynamics and performed altogether ∼1.3 ms of molecular dynamics simulations of fibril elongation for Aβ17–42. Kinetic network analysis of biased simulations resulted in a kinetic model that encompasses all Aβ segments essential for fibril formation. The model not only reproduces key properties of fibril elongation measured in experiments, including Aβ binding affinity, activation enthalpy of Aβ structural transitions and a large time scale gap (τlock/τdock = 103–104) between Aβ binding and its structural transitions, but also reveals detailed pathways involving structural transitions not seen before, namely, fibril formation both in hydrophobic regions L17-A21 and G37-A42 preceding fibril formation in hydrophilic region E22-A30. Moreover, the model identifies as important kinetic intermediates strand–loop–strand (SLS) structures of Aβ monomers, long suspected to be related to fibril elongation. The kinetic model suggests further that fibril elongation arises faster at the fibril tip with exposed L17-A21, rather than at the other tip, explaining thereby unidirectional fibril growth observed previously in experiments.
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Human immunodeficiency virus type 1 (HIV-1) infection is highly dependent on its capsid. The capsid is a large container, made of ∼1,300 proteins with altogether 4 million atoms. Although the capsid ...proteins are all identical, they nevertheless arrange themselves into a largely asymmetric structure made of hexamers and pentamers. The large number of degrees of freedom and lack of symmetry pose a challenge to studying the chemical details of the HIV capsid. Simulations of over 64 million atoms for over 1 μs allow us to conduct a comprehensive study of the chemical-physical properties of an empty HIV-1 capsid, including its electrostatics, vibrational and acoustic properties, and the effects of solvent (ions and water) on the capsid. The simulations reveal critical details about the capsid with implications to biological function.
Single-molecule force experiments in vitro enable the characterization of the mechanical response of biological matter at the nanometer scale. However, they do not reveal the molecular mechanisms ...underlying mechanical function. These can only be readily studied through molecular dynamics simulations of atomic structural models: "in silico" (by computer analysis) single-molecule experiments. Steered molecular dynamics simulations, in which external forces are used to explore the response and function of macromolecules, have become a powerful tool complementing and guiding in vitro single-molecule experiments. The insights provided by in silico experiments are illustrated here through a review of recent research in three areas of protein mechanics: elasticity of the muscle protein titin and the extracellular matrix protein fibronectin; linker-mediated elasticity of the cytoskeleton protein spectrin; and elasticity of ankyrin repeats, a protein module found ubiquitously in cells but with an as-yet unclear function.
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Interplay between cellular membranes and their peripheral proteins drives many processes in eukaryotic cells. Proteins of the Bin/Amphiphysin/Rvs (BAR) domain family, in particular, play a role in ...cellular morphogenesis, for example curving planar membranes into tubular membranes. However, it is still unclear how F-BAR domain proteins act on membranes. Electron microscopy revealed that, in vitro, F-BAR proteins form regular lattices on cylindrically deformed membrane surfaces. Using all-atom and coarse-grained (CG) molecular dynamics simulations, we show that such lattices, indeed, induce tubes of observed radii. A 250 ns all-atom simulation reveals that F-BAR domain curves membranes via the so-called scaffolding mechanism. Plasticity of the F-BAR domain permits conformational change in response to membrane interaction, via partial unwinding of the domains 3-helix bundle structure. A CG simulation covering more than 350 µs provides a dynamic picture of membrane tubulation by lattices of F-BAR domains. A series of CG simulations identified the optimal lattice type for membrane sculpting, which matches closely the lattices seen through cryo-electron microscopy.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
PACE, a hybrid force field that couples united-atom protein models with coarse-grained (CG) solvent (J. Chem. Theory Comput. 2010, 6, 3373), has been further optimized, aiming to improve its ...efficiency for folding simulations. Backbone hydration parameters have been reoptimized based on hydration free energies of polyalanyl peptides through atomistic simulations. Also, atomistic partial charges from all-atom force fields were combined with PACE to provide a more realistic description of interactions between charged groups. Using replica exchange molecular dynamics, ab initio folding using the new PACE has been achieved for seven small proteins (16–23 residues) with different structural motifs. Experimental data about folded states, such as their stability at room temperature, melting point, and nuclear magnetic resonance nuclear Overhauser effect constraints, were also well reproduced. Moreover, a systematic comparison of folding kinetics at room temperature has been made with experiments, through standard molecular dynamics simulations, showing that the new PACE may accelerate the actual folding kinetics 5–10-fold, permitting now the study of folding mechanisms. In particular, we used the new PACE to fold a 73-residue protein, α3D, in multiple 10–30 μs simulations, to its native states (Cα root-mean-square deviation of ∼0.34 nm). Our results suggest the potential applicability of the new PACE for the study of folding and dynamics of proteins.
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The dynamics of excitation energy transfer within the B850 ring of light harvesting complex 2 from Rhodobacter sphaeroides and between neighboring B850 rings is investigated by means of dissipative ...quantum mechanics. The assumption of Boltzmann populated donor states for the calculation of intercomplex excitation transfer rates by generalized Forster theory is shown to give accurate results since intracomplex exciton relaxation to near-Boltzmann population exciton states occurs within a few picoseconds. The primary channels of exciton transfer between B850 rings are found to be the five lowest-lying exciton states, with non-850 nm exciton states making significant contributions to the total transfer rate.
Ring-shaped, hexameric ATPase motors fulfill key functions in cellular processes, such as genome replication, transcription, or protein degradation, by translocating a long substrate through their ...central pore powered by ATP hydrolysis. Despite intense research efforts, the atomic-level mechanism transmitting chemical energy from hydrolysis into mechanical force that translocates the substrate is still unclear. Here we employ all-atom molecular dynamics simulations combined with advanced path sampling techniques and milestoning analysis to characterize how mRNA substrate is translocated by an exemplary homohexameric motor, the transcription termination factor Rho. We find that the release of hydrolysis product (ADP + Pi) triggers the force-generating process of Rho through a 0.1 millisecond-long conformational transition, the time scale seen also in experiment. The calculated free energy profiles and kinetics show that Rho unidirectionally translocates the single-stranded RNA substrate via a population shift of the conformational states of Rho; upon hydrolysis product release, the most favorable conformation shifts from the pretranslocation state to the post-translocation state. Via two previously unidentified intermediate states, the RNA chain is seen to be pulled by six K326 side chains, whose motions are induced by highly coordinated relative translation and rotation of Rho’s six subunits. The present study not only reveals in new detail the mechanism employed by ring-shaped ATPase motors, for example the use of loosely bound and tightly bound hydrolysis reactant and product states to coordinate motor action, but also provides an effective approach to identify allosteric sites of multimeric enzymes in general.
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High resilience to mechanical stress is key when pathogens adhere to their target and initiate infection. Using atomic force microscopy-based single-molecule force spectroscopy, we explored the ...mechanical stability of the prototypical staphylococcal adhesin SdrG, which targets a short peptide from human fibrinogen β. Steered molecular dynamics simulations revealed, and single-molecule force spectroscopy experiments confirmed, the mechanism by which this complex withstands forces of over 2 nanonewtons, a regime previously associated with the strength of a covalent bond. The target peptide, confined in a screwlike manner in the binding pocket of SdrG, distributes forces mainly toward the peptide backbone through an intricate hydrogen bond network. Thus, these adhesins can attach to their target with exceptionally resilient mechanostability, virtually independent of peptide side chains.
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•Cryo-EM is an important tool for structure determination of biomolecular complexes.•Hybrid computational methods combine data from cryo-EM and X-ray crystallography.•MDFF is a highly adaptable ...method for obtaining atomic structures from cryo-EM data.•New MDFF features developed to overcome challenges faced in molecular modeling.
Molecular Dynamics Flexible Fitting (MDFF) is an established technique for fitting all-atom structures of molecules into corresponding cryo-electron microscopy (cryo-EM) densities. The practical application of MDFF is simple but requires a user to be aware of and take measures against a variety of possible challenges presented by each individual case. Some of these challenges arise from the complexity of a molecular structure or the limited quality of available structural models and densities to be interpreted, while others stem from the intricacies of MDFF itself. The current article serves as an overview of the strategies that have been developed since MDFF’s inception to overcome common challenges and successfully perform MDFF simulations.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
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