Electrostatic balance between global repulsion and local attraction in reentrant polymerization of actin

Ohnuki, Jun; Yodogawa, Akira; Takano, Mitsunori

doi:10.1002/cm.21391

Cited by 8 publications

(9 citation statements)

References 35 publications

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“…As with the occupancy simulations of Fig. , studying the kinetics of the profilin‐actin transfer mechanism explicitly would require a detailed model of binding and polymerization . We take here a simpler approach by asking if either FH1 domain can reach out and with what probability to the polyproline binding pocket of profilin at the terminal actin subunit.…”

Section: Resultsmentioning

confidence: 99%

Computational modeling highlights the role of the disordered Formin Homology 1 domain in profilin‐actin transfer

et al. 2018

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Formins accelerate actin polymerization, assumed to occur through flexible FH1 domain mediated transfer of profilin-actin to the barbed end. To study FH1 properties and address sequence effects including varying length/distribution of profilin-binding proline-rich motifs, we performed all-atom simulations of mouse mDia1, mDia2; budding yeast Bni1, Bnr1; fission yeast Cdc12, For3, and Fus1 FH1s. We find FH1 has flexible regions between high propensity polyproline helix regions. A coarse-grained model retaining sequence-specificity, assuming rigid polyproline segments, describes their size. Multiple bound profilins or profilin-actin complexes expand mDia1-FH1, which may be important in cells. Simulations of the barbed end bound to Bni1-FH1-FH2 dimer show the leading FH1 can better transfer profilin or profilin-actin, having decreasing probability with increasing distance from FH2.

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Section: Resultsmentioning

confidence: 99%

Computational modeling highlights the role of the disordered Formin Homology 1 domain in profilin‐actin transfer

et al. 2018

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“…The complex electrostatic interactions of the highly charged actin molecule may also contribute to this effect (39). It has been reported that the actin polymerization ∆H changes sign and ∆S decreases 60-fold as the KCl concentration increases from 30 to 100 mM (55), at which point the critical concentration exhibits a minimum (30). An important factor that we did not include, and which may play a role in enhancing long-pitch helix contacts, is the divalent cation binding at the "polymerization cation site" between subdomains 3 and 4 or at the "stiffness cation site" within the D-loop interface (39).…”

Section: Discussionmentioning

confidence: 99%

Insights into actin polymerization and nucleation using a coarse grained model

Horan

Vavylonis

2019

Preprint

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We studied actin filament polymerization and nucleation with molecular dynamics simulations and a previously established coarse-grained model having each residue represented by a single interaction site located at the C α atom. We approximate each actin protein as a fully or partially rigid unit to identify the equilibrium structural ensemble of interprotein complexes. Monomers in the F-actin configuration bound to both barbed and pointed ends of a short F-actin filament at the anticipated locations for polymerization. Binding at both ends occurred with similar affinity. Contacts between residues of the incoming subunit and the short filament were consistent with expectation from models based on crystallography, X-ray diffraction and cryo-electron microscopy. Binding at the barbed and pointed end also occurred at tilted conformations and the barbed end tilt range was dependent on the flexibility of the D-loop. Additional barbed end bound states were seen when the incoming subunit was in the G form. Consistent with an activation barrier for pointed end polymerization, G-actin did not bind at an F-actin pointed end. In all cases, binding at the barbed end also occurred in a configuration similar to the antiparallel (lower) dimer. Individual monomers bound each other in a short-pitch helix complex in addition to other configurations, with several of them apparently non-productive for polymerization. Simulations with multiple monomers in the F-actin form reproduce filamentation as well as transient aggregates at the barbed end. We discuss the implications on the kinetic pathway of actin filament nucleation and polymerization and possibilities for future improvements of the coarse-grained model. SIGNIFICANCE Control of actin filament polymerization and nucleation has crucial importance to cellular life. We show that coarse-grained molecular dynamics simulations are a powerful tool which can gauge involved mechanisms at reasonable computational cost, while retaining essential features of the fully atomic, yet less computationally tractable, system. Using a knowledge-based potential demonstrates the power of these methods at explaining and reproducing polymerization. Intermediate actin complexes identified in the simulations may play critical roles in the kinetic pathways of actin polymerization which may have been difficult to observe in prior experiments. These methods have been sparsely applied to the actin system, yet have potential to answer many important questions in the field.

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“…ecent studies focusing on interactions of charged proteins in electrolyte solutions have highlighted the interplay of two counteracting electrostatic forces (1)(2)(3)(4). The first one originates from the presence of a localized distribution of charges defining an electrostatic patch on the protein surface.…”

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confidence: 99%

Self-association of a highly charged arginine-rich cell-penetrating peptide

Tesei

Vazdar

Jensen

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Small-angle X-ray scattering (SAXS) measurements reveal a striking difference in intermolecular interactions between two short highly charged peptides-deca-arginine (R10) and deca-lysine (K10). Comparison of SAXS curves at high and low salt concentration shows that R10 self-associates, while interactions between K10 chains are purely repulsive. The self-association of R10 is stronger at lower ionic strengths, indicating that the attraction between R10 molecules has an important electrostatic component. SAXS data are complemented by NMR measurements and potentials of mean force between the peptides, calculated by means of umbrella-sampling molecular dynamics (MD) simulations. All-atom MD simulations elucidate the origin of the R10-R10 attraction by providing structural information on the dimeric state. The last two C-terminal residues of R10 constitute an adhesive patch formed by stacking of the side chains of two arginine residues and by salt bridges formed between the like-charge ion pair and the C-terminal carboxyl groups. A statistical analysis of the Protein Data Bank reveals that this mode of interaction is a common feature in proteins.cell-penetrating peptide | self-association | MD simulations | SAXS | NMR R ecent studies focusing on interactions of charged proteins in electrolyte solutions have highlighted the interplay of two counteracting electrostatic forces (1-4). The first one originates from the presence of a localized distribution of charges defining an electrostatic patch on the protein surface. Depending on relative orientations, the charge distributions in the patches on the protein molecules can become complementary, thereby leading to an attractive electrostatic force (5). This anisotropic force is short ranged and is hereafter referred to as the electrostatic adhesive force. The other force is the double-layer force arising from the Coulombic repulsion between like-charged molecules in the electrolyte medium. Both electrostatic adhesive and double-layer forces are weakened by the presence of salt in the solution. As a nontrivial consequence, the propensity of the proteins to aggregate is heightened at low-to-intermediate ionic strengths (1)(2)(3)6). This is because of lowering of Coulombic repulsion due to salt screening of the net charge of the protein, in conjunction with the presence of the adhesive force, which operates at shorter distances and is therefore less efficiently screened.In this work, the competition between electrostatic adhesive and double-layer forces, together with a chemically specific like-charge attraction between guanidinium (Gdm + ) side-chain groups, is reported for solutions of a small highly charged peptide. Observation of the complex aggregation behavior for a relatively simple molecule is substantiated by a comparative investigation of deca-arginine (R10) and deca-lysine (K10), in high and low ionic strength solutions, conducted using small-angle X-ray scattering (SAXS) measurements, all-atom molecular dynamics (MD) simulations, and 1 H-13 C heteronuclear single...

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Electrostatic balance between global repulsion and local attraction in reentrant polymerization of actin

Cited by 8 publications

References 35 publications

Computational modeling highlights the role of the disordered Formin Homology 1 domain in profilin‐actin transfer

Computational modeling highlights the role of the disordered Formin Homology 1 domain in profilin‐actin transfer

Insights into actin polymerization and nucleation using a coarse grained model

Self-association of a highly charged arginine-rich cell-penetrating peptide

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