Coarse-grained molecular simulations of allosteric cooperativity

Nandigrami, Prithviraj; Portman, John J.

doi:10.1063/1.4943043

Cited by 9 publications

(15 citation statements)

References 49 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…1D) (SI Appendix, Structural Characteristic for Each State). Our results provide a dynamical basis for understanding the previous findings that the C-terminal domain of CaM has a higher affinity to target than the N-terminal domain (14,27,28) and the high plasticity of the linker is determined by its intrinsic flexibility (13)(14)(15)(16). In addition, we used the distributions of rmsd-skMLCK for each state along the pathway to monitor this dynamical process (Fig.…”

Section: Resultsmentioning

confidence: 98%

Molecular mechanism of multispecific recognition of Calmodulin through conformational changes

Liu

Chu

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Calmodulin (CaM) is found to have the capability to bind multiple targets. Investigations on the association mechanism of CaM to its targets are crucial for understanding protein-protein binding and recognition. Here, we developed a structure-based model to explore the binding process between CaM and skMLCK binding peptide. We found the cooperation between nonnative electrostatic interaction and nonnative hydrophobic interaction plays an important role in nonspecific recognition between CaM and its target. We also found that the conserved hydrophobic anchors of skMLCK and binding patches of CaM are crucial for the transition from high affinity to high specificity. Furthermore, this association process involves simultaneously both local conformational change of CaM and global conformational changes of the skMLCK binding peptide. We found a landscape with a mixture of the atypical "induced fit," the atypical "conformational selection," and "simultaneously binding-folding," depending on the synchronization of folding and binding. Finally, we extend our discussions on multispecific binding between CaM and its targets. These association characteristics proposed for CaM and skMLCK can provide insights into multispecific binding of CaM. structure-based model | Calmodulin | mixture binding mechanism | multispecific recognition M any biological processes are driven by protein-protein binding. The large-scale domain rearrangements in proteins have long been recognized to have a critical role in biological function. This flexibility or conformational dynamics also provide a new viewpoint of binding. In addition to the "lock-andkey" binding mechanism, proposed by Fischer to describe the rigid binding in enzyme catalysis (1), two scenarios, considering flexibility during binding, emerged and are referred as "induced fit" and "conformational selection," addressing the critical roles of flexibility in protein recognition (2-6).Calmodulin (CaM) is an ubiquitous Ca 2+ binding protein that is involved in a wide range of cellular Ca 2+ -dependent signaling pathways. With incorporating Ca 2+ ions, Ca 2+ -CaM regulates the activity of many kinds of proteins including protein phosphatase, inositol triphosphate kinase, nitric oxide synthase, protein kinases, nicotinamide adenine dinucleotide kinase, Ca 2+ pumps, and proteins involved in motility (7-9). The binary complex Ca 2+ -CaM is found to have the capability to bind over 300 targets (7)(8)(9). Exploring the molecular mechanism of Ca 2+ -CaM binding to the different targets is crucial for understanding protein-protein multispecific recognition. X-ray crystallography experiments have been performed to resolve Ca 2+ -loaded CaM structure (10). However, complexes of CaM with target enzymes are difficult to study by NMR and the crystallization method, due to the spatial resolution in the experiments. Alternatively, short peptide sequences corresponding to CaM-binding domains are often used to explore CaM-target protein interactions and several studies suggest that these CaM-peptide in...

show abstract

Section: Resultsmentioning

confidence: 98%

Molecular mechanism of multispecific recognition of Calmodulin through conformational changes

Liu

Chu

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

show abstract

“…How this regulation takes place in detail, and what the role of fluctuation allostery is to CaM-CaM dimerisation remains unknown. However, in recent works a range of different types of titration curves were obtained from coarse-grained molecular dynamics 38 , as well as from experiment 7 .…”

Section: Discussionmentioning

confidence: 99%

Ligand-regulated oligomerisation of allosterically interacting proteins

2018

View full text Add to dashboard Cite

The binding of ligands to distinct sites at proteins or at protein clusters is often cooperative or anti-cooperative due to allosteric signalling between those sites. The allostery is usually attributed to a configurational change of the proteins from a relaxed to a configurationally different tense state. Alternatively, as originally proposed by Cooper and Dryden, a tense state may be achieved by merely restricting the thermal vibrations of the protein around its mean configuration. In this work, we provide theoretical tools to investigate fluctuation allostery using cooling and titration experiments in which ligands regulate dimerisation, or ring or chain formation. We discuss in detail how ligands may regulate the supramolecular (co)polymerisation of liganded and unliganded proteins.

show abstract

“…Such an implicit Ca 2+ binding model has been successfully used in previous works to reproduce and explain a number of experimental works on the Ca 2+ binding-coupled folding and the conformational motions of CaM. 30,46…”

Section: Methodsmentioning

confidence: 99%

Consequences of Hydrophobic Nanotube Binding on the Functional Dynamics of Signaling Protein Calmodulin

et al. 2019

View full text Add to dashboard Cite

The wide applications of nanomaterials in industry and our daily life have raised growing concerns on their toxicity to human body. Increasing evidence links the cytotoxicity of nanoparticles to the disruption of cellular signaling pathways. Here, we report a computational study on the mechanisms of the cytotoxicity of carbon nanotubes (CNTs) by investigating the direct impacts of CNTs on the functional motions of calmodulin (CaM), which is one of the most important signaling proteins in a cell, and its signaling function relies on the Ca 2+ binding-coupled conformational switching. Computational simulations with a coarse-grained model showed that binding of CNTs modifies the conformational equilibrium of CaM and induces the closed-to-open conformational transition, leading to the loss of its Ca 2+ -sensing ability. In addition, the binding of CNTs drastically increases the calcium affinity of CaM, which may disrupt the Ca 2+ homeostasis in a cell. These results suggest that the binding of hydrophobic nanotubes not only inhibits the signaling function of CaM as a calcium sensor but also renders CaM to toxic species through sequestering Ca 2+ from other competing calcium-binding proteins, suggesting a new physical mechanism of the cytotoxicity of nanoparticles.

show abstract

Coarse-grained molecular simulations of allosteric cooperativity

Cited by 9 publications

References 49 publications

Molecular mechanism of multispecific recognition of Calmodulin through conformational changes

Molecular mechanism of multispecific recognition of Calmodulin through conformational changes

Ligand-regulated oligomerisation of allosterically interacting proteins

Consequences of Hydrophobic Nanotube Binding on the Functional Dynamics of Signaling Protein Calmodulin

Contact Info

Product

Resources

About