Dynamic protein interfaces and conformational landscapes of membrane protein complexes

Kharche, Shalmali; Sengupta, Durba

doi:10.1016/j.sbi.2020.01.001

Cited by 31 publications

(23 citation statements)

References 60 publications

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“…Potentially, one could also have included the BECN1-BH3D into the 2ABO-apo state within the same simulation box in order to monitor the conformational states as well as mechanisms that ar involved in the binding process. Although such studies for elucidating the binding mechanisms of other protein–protein interactions are common [ 54 , 55 , 56 , 57 ], we note that the size of the simulation box and solvation conditions could have a pronounced effect in terms of drawing scientific conclusions. Further, a recent study by Gapsys and de Groot [ 58 ] also highlighted the importance of considering box width and volume for accurate sampling and estimating kinetics and other relevant parameters.…”

Section: Discussionmentioning

confidence: 99%

Transient Unfolding and Long-Range Interactions in Viral BCL2 M11 Enable Binding to the BECN1 BH3 Domain

et al. 2020

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Viral BCL2 proteins (vBCL2s) help to sustain chronic infection of host proteins to inhibit apoptosis and autophagy. However, details of conformational changes in vBCL2s that enable binding to BH3Ds remain unknown. Using all-atom, multiple microsecond-long molecular dynamic simulations (totaling 17 μs) of the murine γ-herpesvirus 68 vBCL2 (M11), and statistical inference techniques, we show that regions of M11 transiently unfold and refold upon binding of the BH3D. Further, we show that this partial unfolding/refolding within M11 is mediated by a network of hydrophobic interactions, which includes residues that are 10 Å away from the BH3D binding cleft. We experimentally validate the role of these hydrophobic interactions by quantifying the impact of mutating these residues on binding to the Beclin1/BECN1 BH3D, demonstrating that these mutations adversely affect both protein stability and binding. To our knowledge, this is the first study detailing the binding-associated conformational changes and presence of long-range interactions within vBCL2s.

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Section: Discussionmentioning

confidence: 99%

Transient Unfolding and Long-Range Interactions in Viral BCL2 M11 Enable Binding to the BECN1 BH3 Domain

et al. 2020

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“…In solution, proteins fluctuate among many different structures, known also as conformations or conformational substates. [ 29–32 ] A useful framework for understanding this ensemble of conformations is the free‐energy landscape, [ 33–35 ] in which the energy minima represent different conformations and the energy barriers between them dictate the kinetics of conformational exchange. Free‐energy landscapes are multidimensional, [ 36 ] but they are often depicted in only two dimensions for conceptual understanding ( Figure 2 a).…”

Section: Dynamic Energy Landscapes Are Biased Toward the Functionallymentioning

confidence: 99%

Driving Protein Conformational Cycles in Physiology and Disease: “Frustrated” Amino Acid Interaction Networks Define Dynamic Energy Landscapes

2020

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A general framework by which dynamic interactions within a protein will promote the necessary series of structural changes, or “conformational cycle,” required for function is proposed. It is suggested that the free‐energy landscape of a protein is biased toward this conformational cycle. Fluctuations into higher energy, although thermally accessible, conformations drive the conformational cycle forward. The amino acid interaction network is defined as those intraprotein interactions that contribute most to the free‐energy landscape. Some network connections are consistent in every structural state, while others periodically change their interaction strength according to the conformational cycle. It is reviewed here that structural transitions change these periodic network connections, which then predisposes the protein toward the next set of network changes, and hence the next structural change. These concepts are illustrated by recent work on tryptophan synthase. Disruption of these dynamic connections may lead to aberrant protein function and disease states.

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“…In particular, the success of MD simulations is based on the data from the X-ray crystal structure analyses of proteins. Current MD methods can be efficiently employed for proteins with well-packed, stable folds; however, there are many challenges for their use with unstable proteins with structures that are difficult to be analyzed by experiments, e.g., dynamic features of dimerized transmembrane helices 19 and intrinsically disordered proteins. 20 Further validations of this methodology with direct comparison with experimental observations are required.…”

Section: Introductionmentioning

confidence: 99%

All-Atom Molecular Dynamics Elucidating Molecular Mechanisms of Single-Transmembrane Model Peptide Dimerization in a Lipid Bilayer

et al. 2021

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Protein–protein interactions between transmembrane helices are essential elements for membrane protein structures and functions. To understand the effects of peptide sequences and lipid compositions on these interactions, single-molecule experiments using model systems comprising artificial peptides and membranes have been extensively performed. However, their dynamic behavior at the atomic level remains largely unclear. In this study, we applied the all-atom molecular dynamics (MD) method to simulate the interactions of single-transmembrane helical peptide dimers in membrane environments, which has previously been analyzed by single-molecule experiments. The simulations were performed with two peptides (Ala- and Leu-based artificially designed peptides, termed “host peptide”, and the host peptide added with the GXXXG motif, termed “GXXXG peptide”), two membranes (pure-POPC and POPC mixed with 30% cholesterols), and two dimer directions (parallel and antiparallel), consistent with those in the previous experiment. As a result, the MD simulations with parallel dimers reproduced the experimentally observed tendency that introducing cholesterols weakened the interactions in the GXXXG dimer and facilitated those in the host dimer. Our simulation suggested that the host dimer formed hydrogen bonds but the GXXXG dimer did not. However, some discrepancies were also observed between the experiments and simulations. Limitations in the space and time scales of simulations restrict the large-scale undulation and peristaltic motions of the membranes, resulting in differences in lateral pressure profiles. This effect could cause a discrepancy in the rotation angles of helices against the membrane normal.

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Dynamic protein interfaces and conformational landscapes of membrane protein complexes

Cited by 31 publications

References 60 publications

Transient Unfolding and Long-Range Interactions in Viral BCL2 M11 Enable Binding to the BECN1 BH3 Domain

Transient Unfolding and Long-Range Interactions in Viral BCL2 M11 Enable Binding to the BECN1 BH3 Domain

Driving Protein Conformational Cycles in Physiology and Disease: “Frustrated” Amino Acid Interaction Networks Define Dynamic Energy Landscapes

All-Atom Molecular Dynamics Elucidating Molecular Mechanisms of Single-Transmembrane Model Peptide Dimerization in a Lipid Bilayer

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