The physical determinants of the DNA conformational landscape: an analysis of the potential energy surface of single-strand dinucleotides in the conformational space of duplex DNA

Elsawy, K. M.

doi:10.1093/nar/gki888

Cited by 27 publications

(42 citation statements)

References 58 publications

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“…33,54 For the sake of completeness, we briefly describe the algorithm as follows. The 3D ligand spatial density grid is contoured at equally spaced contour intervals that extend from the highest density (strongly interacting with the receptor: diffusively bound regime) to the lowest density (weak/non-interacting: diffusive regime).…”

Section: Resultsmentioning

confidence: 99%

On the interaction mechanisms of a p53 peptide and nutlin with the MDM2 and MDMX proteins: A Brownian dynamics study

et al. 2013

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Inhibition of this interaction has become an important therapeutic strategy in oncology. Although MDM2 and MDMX share a very high degree of sequence/ structural similarity, the small-molecule inhibitor nutlin appears to be an efficient inhibitor only of the p53-MDM2 interaction. Here, we investigate the mechanism of interaction of nutlin with these two proteins and contrast it with that of p53 using Brownian dynamics simulations. In contrast to earlier attempts to examine the bound states of the partners, here we locate initial reaction events in these interactions by identifying the regions of space around MDM2/ MDMX, where p53/nutlin experience associative encounters with prolonged residence times relative to that in bulk solution. We find that the initial interaction of p53 with MDM2 is long-lived relative to nutlin, but, unlike nutlin, it takes place at the N-and C termini of the MDM2 protein, away from the binding site, suggestive of an allosteric mechanism of action. In contrast, nutlin initially interacts with MDM2 directly at the clefts of the binding site.

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Section: Resultsmentioning

confidence: 99%

On the interaction mechanisms of a p53 peptide and nutlin with the MDM2 and MDMX proteins: A Brownian dynamics study

et al. 2013

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“…The basins of attraction within the 3D probability density landscape were then constructed by the contour following algorithm described previously 40,51 .…”

Section: Analysis Of the Bd Simulationsmentioning

confidence: 99%

Recognition Dynamics of p53 and MDM2: Implications for Peptide Design

2016

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Peptides that inhibit MDM2 and attenuate MDM2-p53 interactions, thus activating p53, are currently being pursued as anticancer drug leads for tumors harboring wild type p53. The thermodynamic determinants of peptide-MDM2 interactions have been extensively studied. However, a detailed understanding of the dynamics that underlie these interactions is largely missing. In this study, we explore the kinetics of the binding of a set of peptides using Brownian dynamics simulations. We systematically investigate the effect of peptide C-terminal substitutions (Ser, Ala, Asn, Pro) of a Q16ETFSDLWKLLP27 p53-based peptide and a M1PRFMDYWEGLN12 12/1 phage-derived peptide on their interaction dynamics with MDM2. The substitutions modulate peptide residence times around the MDM2 protein. In particular, the highest affinity peptide, Q16ETFSDLWKLLS27, has the longest residence time (t ∼ 25 μs) around MDM2, suggesting its potentially important contribution to binding affinity. The binding of the p53-based peptides appears to be kinetically driven while that of the phage-derived series appears to be thermodynamically driven. The phage-derived peptides were found to adopt distinctly different modes of interaction with the MDM2 protein compared to their p53-based counterparts. The p53-based peptides approach the N-terminal region of the MDM2 protein with the peptide C-terminal end oriented toward the protein, while the M1PRFMDYWEGLN12-based peptides adopt the reverse orientation. To probe the determinants of this switch in orientation, a designed mutant of the phage-derived peptide, R3E (M1PEFMDYWEGLN12), was simulated and found to adopt the orientation adopted by the p53-based peptides and also to result in almost a 5-fold increase in the peptide residence time (∼120 μs) relative to the p53-based peptides. On this basis, we suggest that the R3E mutant phage-derived peptide has a higher affinity for MDM2 than the p53-based peptides and would therefore, competitively inhibit MDM2-p53. The study, therefore, provides a novel computational framework for kinetics-based lead optimization for anticancer drug development strategies.

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“…For example, they are used in DNA chemistry [1], materials chemistry [2], chemical physics [3], astrophysics [4], etc. .…”

Section: Introductionmentioning

confidence: 99%

Numerical search of discontinuities in self-consistent potential energy surfaces

Dubray

Regnier

2012

Computer Physics Communications

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Potential energy surfaces calculated with self-consistent mean-field methods are a very powerful tool, since their solutions are, in theory, global minima of the non-constrained subspace. However, this minimization leads to an incertitude concerning the saddle points, that can sometimes be no more saddle points in bigger constrained subspaces (fake saddle points), or can be missing on a trajectory (missing saddle points). These phenomena are the consequences of discontinuities of the self-consistent potential energy surfaces (SPES). These discontinuities may have important consequences, since they can for example hide the real height of an energy barrier, and avoid any use of a SPES for further dynamical calculations, barrier penetrability estimations, or trajectory predictions. Discontinuities are not related to the quality of the production of a SPES, since even a perfectly converged SPES with an ideally fine mesh can be discontinuous. In this paper we explain what are the discontinuities, their consequences, and their origins. We then propose a numerical method to detect and identify discontinuities on a given SPES, and finally we discuss what are the best ways to transform a discontinuous SPES into a continuous one.

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The physical determinants of the DNA conformational landscape: an analysis of the potential energy surface of single-strand dinucleotides in the conformational space of duplex DNA

Cited by 27 publications

References 58 publications

On the interaction mechanisms of a p53 peptide and nutlin with the MDM2 and MDMX proteins: A Brownian dynamics study

On the interaction mechanisms of a p53 peptide and nutlin with the MDM2 and MDMX proteins: A Brownian dynamics study

Recognition Dynamics of p53 and MDM2: Implications for Peptide Design

Numerical search of discontinuities in self-consistent potential energy surfaces

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