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Structural analysis of protein dynamics by MD simulations and NMR spin-relaxation.

ABSTRACT: Molecular dynamics (MD) simulations and nuclear magnetic resonance spin-relaxation measurements provide detailed insights into ps-ns structural dynamics of proteins. An analysis of discrepancies between the two methods is presented for the B3 immunoglobulin-binding domain of streptococcal protein G. MD simulations using three MD force fields (OPLS-AA, AMBER ff99SB, and AMBER ff03) overestimate the flexibility of backbone N--H vectors at the borders of secondary structure and in loops when compared with experimentally determined backbone amide generalized order parameters (Hall and Fushman, J Am Chem Soc 2006; 12:7855-7870). Comparison with a previous study of residual dipolar coupling constants (Bouvignies et al., Proc Natl Acad Sci USA 2005;102:13885-13890) indicates that slower timescale motions do not account for the discrepancies. Structural analysis reveals that relative imbalance between the description of hydrogen bonding and other terms of modern force fields may be responsible for disagreement.

SUBMITTER: Trbovic N

PROVIDER: S-EPMC2750878 | biostudies-literature | 2008 May

REPOSITORIES: biostudies-literature

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Structural analysis of protein dynamics by MD simulations and NMR spin-relaxation.

Trbovic Nikola N Kim Byungchan B Friesner Richard A RA Palmer Arthur G AG

Proteins 20080501 2

Molecular dynamics (MD) simulations and nuclear magnetic resonance spin-relaxation measurements provide detailed insights into ps-ns structural dynamics of proteins. An analysis of discrepancies between the two methods is presented for the B3 immunoglobulin-binding domain of streptococcal protein G. MD simulations using three MD force fields (OPLS-AA, AMBER ff99SB, and AMBER ff03) overestimate the flexibility of backbone N--H vectors at the borders of secondary structure and in loops when compar ...[more]

PMID: 17975832

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Project description:BACKGROUND:The role of dynamics in protein functions including signal transduction is just starting to be deciphered. Eph receptors with 16 members divided into A- and B- subclasses are respectively activated by 9 A- and B-ephrin ligands. EphA4 is the only receptor capable of binding to all 9 ephrins and small molecules with overlapped interfaces. RESULTS:We first determined the structures of the EphA4 ligand binding domain (LBD) in two crystals of P1 space group. Noticeably, 8 EphA4 molecules were found in one asymmetric unit and consequently from two crystals we obtained 16 structures, which show significant conformational variations over the functionally critical A-C, D-E, G-H and J-K loops. The 16 new structures, together with previous 9 ones, can be categorized into two groups: closed and open forms which resemble the uncomplexed and complexed structures of the EphA4 LBD respectively. To assess whether the conformational diversity over the loops primarily results from the intrinsic dynamics, we initiated 30-ns molecular dynamics (MD) simulations for both closed and open forms. The results indicate that the loops do have much higher intrinsic dynamics, which is further unravelled by NMR H/D exchange experiments. During simulations, the open form has the RMS deviations slightly larger than those of the closed one, suggesting the open form may be less stable in the absence of external contacts. Furthermore, no obvious exchange between two forms is observed within 30 ns, implying that they are dynamically separated. CONCLUSIONS:Our study provides the first experimental and computational result revealing that the intrinsic dynamics are most likely underlying the conformational diversity observed for the EphA4 LBD loops mediating the binding affinity and specificity. Interestingly, the open conformation of the EphA4 LBD is slightly unstable in the absence of it natural ligand ephrins, implying that the conformational transition from the closed to open has to be driven by the high-affinity interaction with ephrins because the weak interaction with small molecule was found to be insufficient to trigger the transition. Our results therefore highlight the key role of protein dynamics in Eph-ephrin signalling and would benefit future design of agonists/antagonists targeting Eph receptors.

Project description:Backbone (15N) NMR relaxation is one of the main sources of information on dynamics of disordered proteins. Yet, we do not know very well what drives 15N relaxation in such systems, i.e., how different forms of motion contribute to the measurable relaxation rates. To address this problem, we have investigated, both experimentally and via molecular dynamics simulations, the dynamics of a 26-residue peptide imitating the N-terminal portion of the histone protein H4. One part of the peptide was found to be fully flexible, whereas the other part features some transient structure (a hairpin stabilized by hydrogen bonds). The following motional modes proved relevant for 15N relaxation. 1) Sub-picosecond librations attenuate relaxation rates according to S2 ?0.85-0.90. 2) Axial peptide-plane fluctuations along a stretch of the peptide chain contribute to relaxation-active dynamics on a fast timescale (from tens to hundreds of picoseconds). 3) ?/? backbone jumps contribute to relaxation-active dynamics on both fast (from tens to hundreds of picoseconds) and slow (from hundreds of picoseconds to a nanosecond) timescales. The major contribution is from polyproline II (PPII) ? ? transitions in the Ramachandran space; in the case of glycine residues, the major contribution is from PPII ? (?) ? rPPII transitions, in which rPPII is the mirror-image (right-handed) version of the PPII geometry, whereas ? geometry plays the role of an intermediate state. 4) Reorientational motion of certain (sufficiently long-lived) elements of transient structure, i.e., rotational tumbling, contributes to slow relaxation-active dynamics on ?1-ns timescale (however, it is difficult to isolate this contribution). In conclusion, recent advances in the area of force-field development have made it possible to obtain viable Molecular Dynamics models of protein disorder. After careful validation against the experimental relaxation data, these models can provide a valuable insight into mechanistic origins of spin relaxation in disordered peptides and proteins.

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Structural analysis of protein dynamics by MD simulations and NMR spin-relaxation.

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Structural analysis of protein dynamics by MD simulations and NMR spin-relaxation.

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