Conformational Dynamics of Complementarity-determining Region H3 of an Anti-dansyl Fv Fragment in the Presence of its Hapten

Nakasako, Masayoshi; Oka, Toshihiko; Mashumo, Masayasu; Takahashi, Hideo; Shimada, Ichio; Yamaguchi, Yoshiki; Kato, Koichi; Arata, Yoshiaki

doi:10.1016/j.jmb.2005.06.018

Cited by 15 publications

(16 citation statements)

References 35 publications

(51 reference statements)

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“…The protein was thoroughly studied with x-ray crystallography at low temperature and high-quality crystal structures were obtained in different states. 34,35 Because the hydration structures around them were also discussed in their works, it is a good system to compare the calculated hydration structure with experimental one. In this work, the hydration structures around the Fv fragment in unliganded state 34 and around the Fv fragment in complex state with ⑀-dansyl-L-lysine ͑DNS-lys͒ ͑Ref.…”

Section: Hydration Structure Around a Proteinmentioning

confidence: 99%

“…5͑b͔͒, which is consistent with the previous work. 35 In Fig. 6, the bottom of the binding pocket in the complex state was focused to see water oxygen ͑green͒ and water hydrogen ͑white͒.…”

Section: Hydration Structure Around a Proteinmentioning

confidence: 99%

“…These distributions correspond to the water experimentally observed by x-ray diffraction technique at low temperature. 35…”

Section: Hydration Structure Around a Proteinmentioning

confidence: 99%

See 2 more Smart Citations

A highly parallelizable integral equation theory for three dimensional solvent distribution function: Application to biomolecules

Yokogawa

Sato

Imai

et al. 2009

The Journal of Chemical Physics

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Three dimensional (3D) hydration structure is informative to clarify the functions of hydrated waters around a protein. We develop a new approach to calculate 3D solvation structure with reasonable computational cost. In the present method, the total solvation structure is obtained using conventional one dimensional reference interaction site model (RISM) followed by integrating the 3D fragment data, which are evaluated around each atom (site) of solute. Thanks to this strategy, time-consuming 3D fast Fourier transformation, which is required in 3D-RISM theory, can be avoided and high-parallel performance is achieved. The method is applied to small molecular systems for comparison with 3D-RISM. The obtained results by the present method and by 3D-RISM show good agreement. The hydration structures for a large protein computed by the present method are also consistent with those obtained by x-ray crystallography.

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Section: Hydration Structure Around a Proteinmentioning

confidence: 99%

Section: Hydration Structure Around a Proteinmentioning

confidence: 99%

See 1 more Smart Citation

A highly parallelizable integral equation theory for three dimensional solvent distribution function: Application to biomolecules

Yokogawa

Sato

Imai

et al. 2009

The Journal of Chemical Physics

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“…The structural and energetic details of anti‐hapten antibodies have been investigated for a number of low‐molecular weight targets 8–14. These studies have revealed that hapten binding most often occurs at the interface between the heavy and light variable domains (i.e., VH and VL), where the two respective complementarity determining region 3 (CDR3) loops converge.…”

Section: Introductionmentioning

confidence: 99%

An anti‐hapten camelid antibody reveals a cryptic binding site with significant energetic contributions from a nonhypervariable loop

Fanning

Horn

2011

Protein Science

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Conventional anti-hapten antibodies typically bind low-molecular weight compounds (haptens) in the crevice between the variable heavy and light chains. Conversely, heavy chain-only camelid antibodies, which lack a light chain, must rely entirely on a single variable domain to recognize haptens. While several anti-hapten VHHs have been generated, little is known regarding the underlying structural and thermodynamic basis for hapten recognition. Here, an antimethotrexate VHH (anti-MTX VHH) was generated using grafting methods whereby the three complementarity determining regions (CDRs) were inserted onto an existing VHH framework. Thermodynamic analysis of the anti-MTX VHH CDR1-3 Graft revealed a micromolar binding affinity, while the crystal structure of the complex revealed a somewhat surprising noncanonical binding site which involved MTX tunneling under the CDR1 loop. Due to the close proximity of MTX to CDR4, a nonhypervariable loop, the CDR4 loop sequence was subsequently introduced into the CDR1-3 graft, which resulted in a dramatic 1000-fold increase in the binding affinity. Crystal structure analysis of both the free and complex anti-MTX CDR1-4 graft revealed CDR4 plays a significant role in both intermolecular contacts and binding site conformation that appear to contribute toward high affinity binding. Additionally, the anti-MTX VHH possessed relatively high specificity for MTX over closely related compounds aminopterin and folate, demonstrating that VHH domains are capable of binding low-molecular weight ligands with high affinity and specificity, despite their reduced interface.

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“…[8][9][10][11] Also, various antibody-antigen complexes from in silico modeling have been analyzed to reveal an array of interactions between the antibody and antigen and to understand a±nity maturation. [31][32][33][34][35] However, to the best of our knowledge no sig-ni¯cant analysis has been reported on antibody dynamics describing the events that occur just after the¯rst encounter of the antibody with the antigen during primary immune response. Here, we have performed MD simulations on a wide range of structural datasets consisting of antigen-free and antigen-bound structures of germline antibodies 36-65 16 and BBE6.12H3.…”

Section: Discussionmentioning

confidence: 99%

Antigen exposure leads to rigidification of germline antibody combining site

Gill

Jayaswal

Salunke

2014

J. Bioinform. Comput. Biol.

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Immune complexes involving diverse antigens and corresponding antibodies were analyzed for mapping conformational transitions of an antibody before antigen binding, upon antigen binding and after antigen release. Molecular dynamics simulations of the two comprehensive datasets consisting of the antigen-free and antigen-bound structures of the germline antibodies 36-65 and BBE6.12H3 provided mechanistic model of antigen encounter by primary antibodies. While native germline antibodies exhibit substantial mobility in the antigen-combining sites, their antigen-bound states exhibit relatively rigid conformations, even in the absence of the antigen suggesting preservation of the structural state after antigen release. It is proposed that acquired rigidity by a germline antibody upon antigen binding may be the first step in affinity maturation in favor of that antigen.

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Conformational Dynamics of Complementarity-determining Region H3 of an Anti-dansyl Fv Fragment in the Presence of its Hapten

Cited by 15 publications

References 35 publications

A highly parallelizable integral equation theory for three dimensional solvent distribution function: Application to biomolecules

A highly parallelizable integral equation theory for three dimensional solvent distribution function: Application to biomolecules

An anti‐hapten camelid antibody reveals a cryptic binding site with significant energetic contributions from a nonhypervariable loop

Antigen exposure leads to rigidification of germline antibody combining site

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