Protein Ensembles: How Does Nature Harness Thermodynamic Fluctuations for Life? The Diverse Functional Roles of Conformational Ensembles in the Cell

In the paper

“In a typical case, the partial molar volume change is about −20 to −100 mL/mol, which means the free energy change is on the order of −0.5 to −2 kcal/mol per 1 kbar which may be sufficient to shift state B as the dominant species under elevated pressure in place of state A.”

In the paper

“One could estimate that the root mean square fluctuations of E and V are respectively:16 〈ΔE2〉≈38kcalmol−1, 〈ΔV2〉≈80Å3.”

What the sources say

• Not checked yetcites [16] source

In the paper

“The lysine−cysteine distance distribution curve in Fig. 7 (B) displays peaks between 5 and 10 Å, indicating that the two residues are close enough as in acetyltransferase with a Cα−Cα distance of 8.4 Å between Lys262 and Cys304.380”

What the sources say

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In the paper

“Mapping the folding landscape to a single coordinate, such as the fraction of native contacts, the energy landscape can be visualized as a funnel,132 elegantly resolving Levinthal’s paradox.11”

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In the paper

“The more flexible are the proteins the larger the number of their populated states, with the disordered state being at the end of this spectrum.17”

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In the paper

“The statistical energy landscape theory was developed to study protein folding.1,128–131”

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In the paper

“It is now generally accepted that crystal proteins may still have different conformations in a single unit cell,9 and there are multiple, populated substates that are not captured in the crystal state.10”

What the sources say

• Not checked yetcites [9] source
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In the paper

“There are two mechanisms for a protein in solution to attain a lower volume in response to pressure: ‘elastic response’ by general compression within the sub-ensemble of the conformers and a shift of the conformational equilibrium from a high-volume to a low-volume ensemble.”

In the paper

“Protein structures must be considered as dynamic objects at the molecular level due to their intrinsic thermodynamic fluctuations16,92 as well as those of water.93–94”

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In the paper

“Here our thesis is that the distributions of the states on the energy landscape are determined by statistical thermodynamics; however, they are also modulated by function which is optimized by evolution.”

In the paper

“The pivotal concept that all conformations pre-exist and are sampled by thermodynamic fluctuations – with function involving not new conformations but a shift in their relative concentration – underlies current approaches and interpretations.”

What the sources say

• Not checked yetcites [87] source
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In the paper

“The minimum frustration principle implies that nature has optimized protein folding,129,174 thus the effect of point mutations on the energy landscape is analogous to thermal perturbations.175”

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In the paper

“For example, the energy landscape roughness slows down dissociation kinetics and can contribute to streptavidin-biotin interaction dynamic strength.176”

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In the paper

“The energy landscape concept was extended to protein-ligand binding and function87–89,134–141 and statistical approaches were developed to describe the protein binding energy landscape.142–158”

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In the paper

“Exploiting the concept of glasses and supercooled liquids,166 protein motions could be classified by the α fluctuation (primary) and βh fluctuation (secondary).167–168 The slower α relaxation motions are inversely controlled by the solvent viscosity169–170 and the faster βh fluctuations are largely due to the hydration shell of the proteins.171”

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In the paper

“However, long-range contacts in the p53 linker region were required to reproduce the experimental SAXS profile, indicating allosteric communication.227”

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• Not checked yetcites [227] source

In the paper

“mutations at the hinge regions could allosterically affect the binding-site dynamics or induce alternative binding modes by modifying the ensemble of accessible conformations220.”

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In the paper

“The local glass transition temperature TG is proportional to the fluctuation energy, and therefore the protein folding frustration TF/TG is inversely proportional to the fluctuation energy.”

In the paper

“The results indicated that the linker sequence is not randomly distributed; the resulting conformational ensemble of the linker must be optimized for calmodulin binding.234”

What the sources say

• Not checked yetcites [234] source

In the paper

“In the case of p53, phosphorylation at Ser20 turns off p53-MDM2 binding, with a consequent increase in p53 concentration; while phosphorylation at Thr155 targets p53 to degradation by the ubiquitin system (reviewed in256).”

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• Not checked yetcites [256] source

In the paper

“‘Disordered’ or ‘intrinsically unstructured’ proteins lack a stable, well-defined structure under physiological conditions, existing in a continuum of conformations from the less to the more structured states.240–243”

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In the paper

“Many proteins either contain at least one intrinsically disordered region (IDR) (such as intrinsically disordered domains and linkers in multidomain proteins)234,237 or are completely disordered (such as IDPs which are highly flexible and dynamic).238–239”

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In the paper

“The active state of a specific function is a unique state, which is not the case for the inactive states; its stability (population) may increase through a shift of the ensemble, e.g. via binding.”

In the paper

“The conformational ensemble of PaaA2 is highly compact and in solution the protein exists as two preformed helices, connected by a flexible linker where the helices may act as molecular recognition elements for toxin inhibition.259”

What the sources say

• Not checked yetcites [259] source

In the paper

“They identified 10 residues in the interdomain linker region that change their conformations upon substrate binding, including five flexible residues (Met76, Lys77, Thr79, Asp80 and Ser81) and five rigid residues (Arg74, Lys75, Asp78, Glu82 and Glu83).”

What the sources say

• Not checked yetcites [234] source

In the paper

“One such example is the p53 protein, which has more than a dozen phosphorylation and acetylation sites with different biological signals.256”

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• Not checked yetcites [256] source

In the paper

“The structures of disordered proteins are not ‘random’. Rather, the disordered state has significant metastable structures.240–243,257”

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In the paper

“Even though they appear to challenge the paradigm of structural biology, that function requires distinct 3D structure, this is not the case, since function involves a specific selected state, which may have marginal stability and low barriers, thus short residence time which may evade detection.”

In the paper

“The regulation of unstructured proteins in the cell can occur at multiple levels of mRNA transcription and degradation; protein translation and degradation; and fidelity control of transcription and translation, including post-translational modifications in functional/degradation control.254”

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In the paper

“The combination of optimal length, IL flexibility, and specific contacts between the IL and interface are needed to stabilize the active state.”

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• Not checked yetcites [236] source

In the paper

“It was suggested that anti-correlation of the distances between each C-terminal domain and the anchor promotes the function of L12 to recruit translation factors and control their activity on the ribosome.235”

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• Not checked yetcites [235] source

In the paper

“Intrinsically disordered linkers connecting folded domains and intrinsically disordered domains usually encode the degrees of conformational flexibility essential for protein function,17,29,244–250,239,247,249–253 including regulation of transcription and translation, cellular signaling, phosphorylation, regulation of large multi-molecular self-assemblies and small molecule storage.249”

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In the paper

“The ‘induced fit’ hypothesis412 suggests that the bound conformation can be ‘induced’ by the binding partner when the conformation in the complexes differs from that in the unbound form.”

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• Not checked yetcites [412] source

In the paper

“demonstrated that the conformational ensembles of histone tails are composed of states with various degrees of residual order and most tails are not fully disordered, but show distinct conformational organization, containing α-helical elements and β-hairpins.368”

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• Not checked yetcites [368] source

In the paper

“Overall, these studies revealed the potential of MSMs to identify putative allosteric binding sites or to differentiate between agonists and antagonists using conformational information along putative functional pathways.”

In the paper

“Oligomeric proteins with two or more subunits comprise about one third of the cellular proteins,266–267 most of them symmetrical.266”

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In the paper

“IDPs adopt multiple conformations for function;377–378 that is, the multiple conformational ensembles collectively determine functions.”

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In the paper

“Markov state models have been applied to a wide variety of problems, spanning protein folding,402 protein-ligand binding process,403 protein conformational change,404–405 the dynamics and kinetics of IDPs,369,406–407 and ATP permeation through membrane protein channels.408”

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In the paper

“Proteins and their binding partners are flexible and exist in ensembles with certain conformational distributions.”

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In the paper

“Similar to the REMD method, metadynamics is also an enhanced sampling method which is widely used to explore the conformational space of biomolecules.314,381”

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In the paper

“Enhanced sampling methods such as REMD and metadynamics can provide the structural and thermodynamic properties of proteins. However, they do not reproduce kinetic rates and conformational dynamics.”

In the paper

“Acetylation of tau inhibits its function and promotes pathological aggregation.373–375”

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In the paper

“Molecular dynamics simulations of CypA show that the ensembles of enzyme conformations recognize diverse inhibitors and bind different configurations of the peptide substrate.3”

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• Not checked yetcites [3] source

In the paper

“GPCRs exhibit multiple inactive and active conformations, and the population balance between these conformations is altered upon binding of ligands.415”

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• Not checked yetcites [415] source

In the paper

“The protein conformational ensemble not only allows enzymes to catalyze multiple chemical steps, but accommodates the conformational reorganization required to stabilize the transition states.449”

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In the paper

“The docking algorithm was validated on 10 protein ensembles containing 105 crystal structures and 87 ligands and achieved a success rate of 93%, significantly better than single rigid-receptor docking (75% on average).425”

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In the paper

“Therefore, receptor activation depends on both low energy states and the range of the conformations sampled by the receptor.416”

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In the paper

“An earlier QM/MM study468 demonstrated that R55K substitution at the active site of CypA leads to a significant decrease in catalysis, indicating that the active site stability likely plays an important role in the chemical step of catalysis.”

What the sources say

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In the paper

“It has been shown that ligands can interact with similar targets in different conformations, and that the biological outcomes like ERβ selective agonist depend on the relative affinities of a ligand to ensembles of protein conformations.414”

What the sources say

• Not checked yetcites [414] source

In the paper

“Comparison of the apo and holo equilibrium ensembles reveals that c-Myc binding conformations are already partially formed in the apo ensemble, suggesting a conformational selection mechanism.432”

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• Not checked yetcites [432] source

In the paper

“This correlation could suggest that protein motions necessary for catalysis are an intrinsic property of the enzyme and might even limit the overall turnover rate.469”

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In the paper

“The conformational ensemble and population shift allow the enzyme to bind the co-substrate prior to the substrate, and can also limit premature release of substrate.442”

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In the paper

“The disordered state has a significant metastable structure character240–243,257 and functionally relevant conformations may have population times higher than of other conformations.240–242”

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In the paper

“They found that promiscuous residues tend to be more flexible, and this additional flexibility permits a broader range of organizations which could take place in different conformers in the ensemble.523”

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In the paper

“Obviously, the most flexible proteins are the disordered proteins, with some more folded than others.525”

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In the paper

“This bias implies that they adopt an ensemble of disordered and partially helical conformations, with the latter becoming stabilized when these proteins form complexes, depending on pH and concentration.527”

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In the paper

“Often, weak complexes have smaller contact area and the interfaces are more planar and with more polar residues,511”

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In the paper

“Even though antibody-antigen interfaces have fewer hot spot residues,496,518 Tyr is a preferred hot spot residue for immunoglobulins.119a”

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In the paper

“Dynamic conformational changes during the Eph-ephrin recognition were found to be stepwise conformational selection and population shift events, with two dynamic salt bridges between EphB4 and Ephrin-B2 contributing to specific recognition.”

What the sources say

• Not checked yetcites [514] source

In the paper

“Some associations are obligatory where one protein is bound to another throughout its functional lifetime, whereas others are transient, continuously forming and dissociating503–510.”

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In the paper

“For example, the interactions of nidogen-1 with laminin variants indicate the existence of a conformational ensemble of both individual proteins and complex, implying different modes of interaction through distinct protein-protein interfaces.522”

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In the paper

“Centrosomal proteins tend to be larger than a control set of human proteins, and are rich in predicted disordered regions, which cover 57% of their length, compared to 39% in the general human proteome.526”

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• Not checked yetcites [526] source

In the paper

“the binding affinities of EphA4 with ephrin-A1, ephrin-A2, ephrin-A4, ephrin-A5, and ephrin-B2 are 1.2 μm, 2.3 μm, 36 nm, 360 nm, and 10.8 μm, respectively,512 indicating varied selectivity towards various ligands.”

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In the paper

“Such a cellular strategy facilitates variable response to the environment and gain of function in network evolution.535”

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In the paper

“Interestingly, protein disorder in the centrosome correlates with complexity with the number of cell types, and the structural heterogeneity conferred by the disordered regions and phosphorylation playing an important role in its mechanical properties and regulation in space and time.528”

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In the paper

“Since RNA and DNA carry generic information, protein-RNA/DNA interactions should ensure correct processing of genomic information.”

In the paper

“When unphosphorylated and unbound, KID is disordered. Cooperative folding and binding occur upon pKID–KIX interaction, forming two α-helices kinked near the phosphorylated site.529”

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