Rigid Residue Scan Simulations Systematically Reveal Residue Entropic Roles in Protein Allostery

Kalescky, Robert; Zhou, Haoming; Liu, Jin; Tao, Peng

doi:10.1371/journal.pcbi.1004893

Cited by 32 publications

(51 citation statements)

References 89 publications

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“…In addition, 30 ns trajectory was carried out for each RRS simulation to be consistent with unperturbed simulations. Our previous study also support that the 30 ns trajectories are sufficient to probe protein allosteric mechanisms34.…”

Section: Discussionsupporting

confidence: 80%

Revealing Hidden Conformational Space of LOV Protein VIVID Through Rigid Residue Scan Simulations

Zhou

Zoltowski

Tao

2017

Sci Rep

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VIVID(VVD) protein is a Light-Oxygen-Voltage(LOV) domain in circadian clock system. Upon blue light activation, a covalent bond is formed between VVD residue Cys108 and its cofactor flavin adenine dinucleotide(FAD), and prompts VVD switching from Dark state to Light state with significant conformational deviation. However, the mechanism of this local environment initiated global protein conformational change remains elusive. We employed a recently developed computational approach, rigid residue scan(RRS), to systematically probe the impact of the internal degrees of freedom in each amino acid residue of VVD on its overall dynamics by applying rigid body constraint on each residue in molecular dynamics simulations. Key residues were identified with distinctive impacts on Dark and Light states, respectively. All the simulations display wide range of distribution on a two-dimensional(2D) plot upon structural root-mean-square deviations(RMSD) from either Dark or Light state. Clustering analysis of the 2D RMSD distribution leads to 15 representative structures with drastically different conformation of N-terminus, which is also a key difference between Dark and Light states of VVD. Further principle component analyses(PCA) of RRS simulations agree with the observation of distinctive impact from individual residues on Dark and Light states.

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Section: Discussionsupporting

confidence: 80%

Revealing Hidden Conformational Space of LOV Protein VIVID Through Rigid Residue Scan Simulations

Zhou

Zoltowski

Tao

2017

Sci Rep

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“…Recently, a few computational and experimental reports suggested that La Châtelier's principle may be behind dynamic allostery. Using a rigid residue scan molecular dynamics simulation-based method, Kalescky et al (20,21) reported that decreasing local entropy by increasing individual residue rigidity of PDZ domain proteins often leads to increasing global configurational entropy. Recently, biophysical experiments performed by Law et al (22) revealed that the volume of PDZ3 domain protein is coupled with local internal motion, following La Châtelier's principle.…”

mentioning

confidence: 99%

Energetic redistribution in allostery to execute protein function

Liu

Nussinov

2017

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

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A perturbation at one site of the protein could cause an effect at a distant site. This important biological phenomenon, termed the "allosteric effect," is essential for protein regulation and cell signaling, playing an important role in cellular function. Its fundamental functional significance has inspired numerous works aiming to understand how allostery works. Allostery can involve large, or unobserved, subtle (mainly side-chain) conformational changes (1). Conformational changes are driven by enthalpy. The term "dynamic allostery" was coined by Cooper and Dryden in the early 1980s to describe allostery "even in the absence of a macromolecular conformational change" (2). Cooper and Dryden argued that dynamic allostery is primarily an entropy effect. However, numerous works have been published over the last 20 y taking "dynamic allostery" to imply a complete absence of conformational change because the authors did not observe such changes (1). Importantly, "dynamic allostery" without observable conformational changes is still ruled by a population shift between two "distinct" states where a new energetic redistribution favorable for the allosteric (functional) state is either dominated by entropy, enthalpy, or both. Few studies questioned whether enthalpy plays a role in dynamic allostery as well (1). In PNAS, Kumawat and Chakrabarty (3) demonstrate that indeed even in dynamic allostery enthalpy plays a role by redistributing internal energies, especially electrostatic interaction energies, among residues upon perturbation (Fig. 1).Electrostatics is an established player in function. Decades ago, Warshel (4) and Warshel et al. (5) demonstrated its critical role in protein catalysis and Perutz (6) in allostery. Recently, rearrangements of electrostatic networks were reported for conformationally driven allostery (7,8). The report of hidden electrostatic interactions in dynamic allostery in PNAS (3) argues that redistribution of electrostatic interaction energy could be universal in allosteric proteins, with or without significant conformational change.Proteins embrace redistribution of electrostatic interaction energies to execute their functions. For example, myosin, a motor protein, binds to the negatively charged ATP, which redistributes the electrostatic bond network, thus altering the charge of the actin-binding site, leading to myosin's dissociation from actin (7). Thus, myosin redistributes electrostatic interaction energy in allostery to execute its function of dissociation from actin.The PDZ domain protein is a well-known cell signaling protein. The major functions of PDZ domains include recognition of the disordered C-terminal peptide motifs of hundreds of receptors and ion-channel proteins, dimerization with other modular domains, and phospholipid binding. As a dynamic regulator of cell signaling, PDZ function can be modulated allosterically (9). In the PDZ3 domain protein, the peptide recognition site is located at the hydrophobic β2-α2 region. Mutations of distal residues on the PDZ3 domain or del...

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“…To demonstrate our SVD‐based correlation analysis of allosteric proteins, we apply the method to the PDZ2 domain in hPTP1E, a model system in allosteric studies containing 94 residues (PDB ID 3LNY). The conformation ensemble was sampled by MD simulations of a coarse‐grained Gō‐like model (see Methods).…”

Section: Resultsmentioning

confidence: 99%

“…The analysis reveals that significant inter‐residue and inter‐domain couplings as well as the allosteric response can be inferred from correlated atomic fluctuations. Conventionally, the cross‐correlations of atoms or residues are measured by the DP form of the correlation coefficient, defined as

C_{ij}^{(DP)} = \frac{〈Δ {boldr}_{i} \cdot Δ {boldr}_{j}〉}{{〈{|Δ {boldr}_{i}|}^{2}〉}^{\frac{1}{2}} {〈{|Δ {boldr}_{j}|}^{2}〉}^{\frac{1}{2}}},

where Δ r i and Δ r j are the displacements of residues (atoms) i and j from their average positions, respectively. Here, the superscript “DP” distinguishes the DP correlation coefficient from the proposed correlation coefficient (defined below).…”

Section: Introductionmentioning

confidence: 99%

Singular value decomposition for the correlation of atomic fluctuations with arbitrary angle

Cao

et al. 2018

Proteins

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Many proteins exhibit a critical property called allostery, which enables intra-molecular transmission of information between distal sites. Microscopically, allosteric response is closely related to correlated atomic fluctuations. Conventional correlation analysis correlates the atomic fluctuations at two sites by taking the dot product (DP) between the fluctuations, which accounts only for the parallel and antiparallel components. Here, we present a singular value decomposition (SVD) method that analyzes the correlation coefficient of fluctuation dynamics with an arbitrary angle between the correlated directions. In a model allosteric system, the second PDZ domain (PDZ2) in the human PTP1E protein, approximately one third of the strong correlations have near-perpendicular directions, which are underestimated in the conventional method. The discrimination becomes more prominent for residue pairs with larger separation. The results of the proposed SVD method are more consistent with the experimentally determined PDZ2 dynamics than those of conventional method. In addition, the SVD method improved the prediction accuracy of the allosteric sites in a dataset of 23 known allosteric monomer proteins. The proposed method may inspire extended investigation not only into allostery, but also into protein dynamics and drug design.

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Rigid Residue Scan Simulations Systematically Reveal Residue Entropic Roles in Protein Allostery

Cited by 32 publications

References 89 publications

Revealing Hidden Conformational Space of LOV Protein VIVID Through Rigid Residue Scan Simulations

Revealing Hidden Conformational Space of LOV Protein VIVID Through Rigid Residue Scan Simulations

Energetic redistribution in allostery to execute protein function

Singular value decomposition for the correlation of atomic fluctuations with arbitrary angle

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