Brownian Dynamics Simulation of Protein–Protein Diffusional Encounter

Gabdoulline, Razif R.; Wade, Rebecca C.

doi:10.1006/meth.1998.0588

Cited by 171 publications

(191 citation statements)

References 53 publications

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“…Fortunately, a computational modeling study of the human PCNA-Ub complex, which was already in progress, provided alternative models for the PCNA-Ub complex and these computational results could be directly incorporated into the experimental SAXS investigation. The computational modeling involved a combination of tethered Brownian dynamics (TBD) (20), protein-protein docking with RosettaDock (a component of the ROSETTA++ software package) (21)(22)(23)(24)(25), flexible loop modeling with ModLoop (26,27), and molecular dynamics (Fig. S1).…”

Section: Resultsmentioning

confidence: 99%

Solution X-ray scattering combined with computational modeling reveals multiple conformations of covalently bound ubiquitin on PCNA

Tsutakawa

Wynsberghe

Freudenthal

et al. 2011

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

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PCNA ubiquitination in response to DNA damage leads to the recruitment of specialized translesion polymerases to the damage locus. This constitutes one of the initial steps in translesion synthesis (TLS)-a critical pathway for cell survival and for maintenance of genome stability. The recent crystal structure of ubiquitinated PCNA (Ub-PCNA) sheds light on the mode of association between the two proteins but also revealed that paradoxically, the ubiquitin surface engaged in PCNA interactions was the same as the surface implicated in translesion polymerase binding. This finding implied a degree of flexibility inherent in the Ub-PCNA complex that would allow it to transition into a conformation competent to bind the TLS polymerase. To address the issue of segmental flexibility, we combined multiscale computational modeling and small angle X-ray scattering. This combined strategy revealed alternative positions for ubiquitin to reside on the surface of the PCNA homotrimer, distinct from the position identified in the crystal structure. Two mutations originally identified in genetic screens and known to interfere with TLS are positioned directly beneath the bound ubiquitin in the alternative models. These computationally derived positions, in an ensemble with the crystallographic and flexible positions, provided the best fit to the solution scattering, indicating that ubiquitin dynamically associated with PCNA and is capable of transitioning between a few discrete sites on the PCNA surface. The finding of new docking sites and the positional equilibrium of PCNA-Ub occurring in solution provide unexpected insight into previously unexplained biological observations. SAXS | DNA replication | DNA repair | mutagenesis C lassical DNA polymerases-those involved in normal DNA replication and repair-cannot accommodate many types of DNA damage in the template strand. As a result, replication forks stall when encountering DNA damage, and this is one of the major sources of genome instability. One of the principal pathways for overcoming replication blocks is translesion synthesis (TLS) by one of a variety of specialized TLS polymerases (1-4). These TLS synthesis polymerases are recruited to stalled replication forks where they replace the classical polymerase and carry out DNA synthesis across from the DNA damage. DNA polymerase eta (pol η), for example, replicates efficiently and accurately through thymine dimers and 8-oxoguanine lesions (5, 6). Significant insights into how TLS polymerases accommodate DNA damage have come from structural and kinetic studies of these enzymes over the last decade (2, 4).Arguably the least understood steps of translesion synthesis are the recruitment of the TLS polymerase to stalled replication forks and the subsequent polymerase switch between the stalled classical polymerase and the TLS polymerase. These steps are governed by the monoubiquitylation of proliferating cell nuclear antigen (PCNA). PCNA is monoubiquitylated on Lys-164 by the Rad6-Rad18 complex in response to DNA damage (7,8). The at...

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Section: Resultsmentioning

confidence: 99%

Solution X-ray scattering combined with computational modeling reveals multiple conformations of covalently bound ubiquitin on PCNA

Tsutakawa

Wynsberghe

Freudenthal

et al. 2011

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

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“…The encounter complex, a diffusively bound state that forms prior to any (nondiffusive, classical) bound complex, is characterized by regions of the proteinligand interaction landscape where associative interactions dominate over dissociative interactions. 36,[41][42][43][44][45][46] These regions of space, termed basins of attraction, correspond to molecular configurations whose lifetime (residence time) is prolonged relative to those in the bulk environment, but are not bound to the protein surface. 36 In the following sections, we use p53 to refer to a set of p53 peptides in their wild type and phosphorylated states and we use MDM2 to refer to the crystallized N-terminal domain of MDM2 (from residues 25-109).…”

Section: Resultsmentioning

confidence: 99%

“…The BD trajectories were propagated by solving the translational and the rotational diffusion equations, using the Ermak-McCammon algorithm 53 as implemented in the SDA package version 4.23 b. 42 The translational and rotational diffusion coefficients were calculated using the HYDROPRO software. 54 Initially, the center of mass (COM) of the protein was placed at the origin, and the ligand was placed at b D 150.0 A COM-COM separation relative to the protein COM.…”

Section: Modeling the Ligand Protein Diffusional Associationmentioning

confidence: 99%

“…42,52 In order to get a detailed picture of the ligand protein interaction landscape, a 201 £ 201 £ 201 A 3D spatial probability density grid with a spacing of 1 A was constructed around the protein by computing the average frequency of the ligand COM visiting individual spatial grid cells. The basins of attraction within the 3D grid were detected by the contour following algorithm described previously.…”

Section: Analysis Of the Bd Simulationsmentioning

confidence: 99%

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A spatiotemporal characterization of the effect of p53 phosphorylation on its interaction with MDM2

et al. 2015

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T he interaction of p53 and MDM2 is modulated by the phosphorylation of p53. This mechanism is key to activating p53, yet its molecular determinants are not fully understood. To study the spatiotemporal characteristics of this molecular process we carried out Brownian dynamics simulations of the interactions of the MDM2 protein with a p53 peptide in its wild type state and when phosphorylated at Thr18 (pThr18) and Ser20 (pSer20). We found that p53 phosphorylation results in concerted changes in the topology of the interaction landscape in the diffusively bound encounter complex domain. These changes hinder phosphorylated p53 peptides from binding to MDM2 well before reaching the binding site. The underlying mechanism appears to involve shift of the peptide away from the vicinity of the MDM2 protein, peptide reorientation, and reduction in peptide residence time relative to wild-type p53 peptide. pThr18 and pSr20 p53 peptides experience reduction in residence times by factors of 13.6 and 37.5 respectively relative to the wild-type p53 peptide, indicating a greater role for Ser20 phosphorylation in abrogating p53 MDM2 interactions. These detailed insights into the effect of phosphorylation on molecular interactions are not available from conventional experimental and theoretical approaches and open up new avenues that incorporate molecular interaction dynamics, for stabilizing p53 against MDM2, which is a major focus of anticancer drug lead development.

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“…In many applications (e.g., proteins dynamics [12,14,20]) DNS, by means of the classical Euler-Maruyama scheme, is the method of choice, although it is well known that it is biased and, specifically, does not preserve reversibility (for details see Section 3.3.2).…”

Section: Sampling the Invariant Distributionmentioning

confidence: 99%

A structure-preserving numerical discretization of reversible diffusions

Latorre

Metzner

Hartmann

et al. 2011

Communications in Mathematical Sciences

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Abstract. We propose a numerical discretization scheme for the infinitesimal generator of a diffusion process based on a finite volume approximation. The resulting discrete-space operator can be interpreted as a jump process on the mesh whose invariant distribution is precisely the cell approximation of the Boltzmann invariant measure and preserves the detailed balance property of the original stochastic process. Moreover this approximation is robust in the sense that these properties remain valid independently of the grid size.

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Brownian Dynamics Simulation of Protein–Protein Diffusional Encounter

Cited by 171 publications

References 53 publications

Solution X-ray scattering combined with computational modeling reveals multiple conformations of covalently bound ubiquitin on PCNA

Solution X-ray scattering combined with computational modeling reveals multiple conformations of covalently bound ubiquitin on PCNA

A spatiotemporal characterization of the effect of p53 phosphorylation on its interaction with MDM2

A structure-preserving numerical discretization of reversible diffusions

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