Dataset Information

Heterogeneous Solvation in Distinctive Protein-Protein Interfaces Revealed by Molecular Dynamics Simulations.

ABSTRACT: Water, despite being a driving force in biochemical processes, has an elusively complex microscopic behavior. While water can increase its local density near amphiphilic protein surfaces, water is also thought to evaporate from hydrophobic surfaces and cavities, an effect known as "dewetting". The existence and extent of dewetting effects remains elusive due to the difficulty in observing clear "drying" transitions in experiments or simulations. Here, we use explicit solvent molecular dynamics (MD) simulations to study the molecular solvation at the binding interfaces of two distinctive molecular complexes: the highly hydrophilic barnase-barstar and the highly hydrophobic MDM2-p53. Our simulations, in conjunction with simple volumetric analyses, reveal a strikingly different water behavior at the binding interfaces of these two molecular complexes. In both complexes, we observe significant changes in the water local density as the two proteins approach, supporting the existence of a clear dewetting transition in the case of MDM2-p53, with an onset distance of 5.6-7.6 Å. Furthermore, the solvation analysis reported herein is a valuable tool to capture and quantify persistent or transient dewetting events in future explicit solvent MD simulations.

SUBMITTER: Ricci CG

PROVIDER: S-EPMC6713198 | biostudies-literature | 2018 Dec

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Heterogeneous Solvation in Distinctive Protein-Protein Interfaces Revealed by Molecular Dynamics Simulations.

Ricci Clarisse G CG McCammon J Andrew JA

The journal of physical chemistry. B 20181009 49

Water, despite being a driving force in biochemical processes, has an elusively complex microscopic behavior. While water can increase its local density near amphiphilic protein surfaces, water is also thought to evaporate from hydrophobic surfaces and cavities, an effect known as "dewetting". The existence and extent of dewetting effects remains elusive due to the difficulty in observing clear "drying" transitions in experiments or simulations. Here, we use explicit solvent molecular dynamics ( ...[more]

PMID: 30252476

Similar Datasets

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.

Dataset Information

Heterogeneous Solvation in Distinctive Protein-Protein Interfaces Revealed by Molecular Dynamics Simulations.

Publications

Heterogeneous Solvation in Distinctive Protein-Protein Interfaces Revealed by Molecular Dynamics Simulations.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets