Cooperative Protein Allosteric Transition Mediated by a Fluctuating Transmission Network

Post, Matthias; Lickert, Benjamin; Diez, Georg; Wolf, Steffen; Stock, Gerhard

doi:10.1016/j.jmb.2022.167679

Cited by 13 publications

(21 citation statements)

References 59 publications

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“…In particular, the 27 highly correlated contact distances of cluster 1 are found to describe the functional open-closed transition of T4L. This is illustrated in Figure c, which shows that these distances span the space connecting the mouth and hinge regions and therefore reflect the allosteric coupling between these two distant regions . Largely uncorrelated to cluster 1, clusters 2 and 3 account for other correlated motions of T4L.…”

Section: Applicationsmentioning

confidence: 86%

“…This is illustrated in Figure 3c, which shows that these distances span the space connecting the mouth and hinge regions and therefore reflect the allosteric coupling between these two distant regions. 73 Largely uncorrelated to cluster 1, clusters 2 and 3 account for other correlated motions of T4L. As shown in Figure 3d, cluster 2 describes a rocking motion involving the rearrangement of α 1 and the N-terminal domain, while cluster 3 contains a twist-like motion of the β-sheets and the α 2 -helix close by.…”

Section: Applicationsmentioning

confidence: 92%

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Correlation-Based Feature Selection to Identify Functional Dynamics in Proteins

Diez

Nagel

Stock

2022

J. Chem. Theory Comput.

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To interpret molecular dynamics simulations of biomolecular systems, systematic dimensionality reduction methods are commonly employed. Among others, this includes principal component analysis (PCA) and time-lagged independent component analysis (TICA), which aim to maximize the variance and the time scale of the first components, respectively. A crucial first step of such an analysis is the identification of suitable and relevant input coordinates (the so-called features), such as backbone dihedral angles and interresidue distances. As typically only a small subset of those coordinates is involved in a specific biomolecular process, it is important to discard the remaining uncorrelated motions or weakly correlated noise coordinates. This is because they may exhibit large amplitudes or long time scales and therefore will be erroneously considered important by PCA and TICA, respectively. To discriminate collective motions underlying functional dynamics from uncorrelated motions, the correlation matrix of the input coordinates is block-diagonalized by a clustering method. This strategy avoids possible bias due to presumed functional observables and conformational states or variation principles that maximize variance or time scales. Considering several linear and nonlinear correlation measures and various clustering algorithms, it is shown that the combination of linear correlation and the Leiden community detection algorithm yields excellent results for all considered model systems. These include the functional motion of T4 lysozyme to demonstrate the successful identification of collective motion, as well as the folding of the villin headpiece to highlight the physical interpretation of the correlated motions in terms of a functional mechanism.

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Section: Applicationsmentioning

confidence: 86%

Section: Applicationsmentioning

confidence: 92%

Correlation-Based Feature Selection to Identify Functional Dynamics in Proteins

Diez

Nagel

Stock

2022

J. Chem. Theory Comput.

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“…On the other hand, we expect that the main finding, i.e., that allosteric communication is mediated through a concerted conformational transition that involves numerous simultaneous contact changes, prevails also in the absence of direct contacts and therefore represents a general result. For example, Post et al 44 found a quite similar scenario for the allosteric coupling in T4 lysozyme.…”

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confidence: 92%

“…That is, all contacts change almost simultaneously, similar to the cooperative mechanism that was observed in the functional dynamics of T4 lysozyme. 44 As for T4L, the cooperative mechanism may be rationalized by an Ising-type model, 49 where local couplings between two-state entities (i.e., the contacts) lead to the emergence of well-defined global states of the system. Starting in the relatively ordered cis state, the system becomes disordered upon cis-to-trans photoswitching and returns to an ordered state via a cooperative transition.…”

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confidence: 99%

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Nonequilibrium Modeling of the Elementary Step in PDZ3 Allosteric Communication

Ali

Gulzar

Wolf

et al. 2022

J. Phys. Chem. Lett.

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While allostery is of paramount importance for protein signaling and regulation, the underlying dynamical process of allosteric communication is not well understood. The PDZ3 domain represents a prime example of an allosteric single-domain protein, as it features a well-established long-range coupling between the C-terminal α3-helix and ligand binding. In an intriguing experiment, Hamm and co-workers employed photoswitching of the α3-helix to initiate a conformational change of PDZ3 that propagates from the C-terminus to the bound ligand within 200 ns. Performing extensive nonequilibrium molecular dynamics simulations, the modeling of the experiment reproduces the measured time scales and reveals a detailed picture of the allosteric communication in PDZ3. In particular, a correlation analysis identifies a network of contacts connecting the α3-helix and the core of the protein, which move in a concerted manner. Representing a one-step process and involving direct α3-ligand contacts, this cooperative transition is considered as the elementary step in the propagation of conformational change.

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Gating residues govern ligand unbinding kinetics from the buried cavity in HIF‐2α PAS‐B

Silvestrini,

Solazzo,

Boral

et al. 2024

Protein Science

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While transcription factors have been generally perceived as “undruggable,” an exception is the HIF‐2 hypoxia‐inducible transcription factor, which contains an internal cavity that is sufficiently large to accommodate a range of small‐molecules, including the therapeutically used inhibitor belzutifan. Given the relatively long ligand residence times of these small molecules and the lack of any experimentally observed pathway connecting the cavity to solvent, there has been great interest in understanding how these drug ligands exit the buried receptor cavity. Here, we focus on the relevant PAS‐B domain of hypoxia‐inducible factor 2α (HIF‐2α) and examine how one such small molecule (THS‐017) exits from the buried cavity within this domain on the seconds‐timescale using atomistic simulations and ZZ‐exchange NMR. To enable the simulations, we applied the weighted ensemble path sampling strategy, which generates continuous pathways for a rare‐event process [e.g., ligand (un)binding] with rigorous kinetics in orders of magnitude less computing time compared to conventional simulations. Results reveal the formation of an encounter complex intermediate and two distinct classes of pathways for ligand exit. Based on these pathways, we identified two pairs of conformational gating residues in the receptor: one for the major class (N288 and S304) and another for the minor class (L272 and M309). ZZ‐exchange NMR validated the kinetic importance of N288 for ligand unbinding. Our results provide an ideal simulation dataset for rational manipulation of ligand unbinding kinetics.

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Cooperative Protein Allosteric Transition Mediated by a Fluctuating Transmission Network

Cited by 13 publications

References 59 publications

Correlation-Based Feature Selection to Identify Functional Dynamics in Proteins

Correlation-Based Feature Selection to Identify Functional Dynamics in Proteins

Nonequilibrium Modeling of the Elementary Step in PDZ3 Allosteric Communication

Gating residues govern ligand unbinding kinetics from the buried cavity in HIF‐2α PAS‐B

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