Effects of pH on an IDP conformational ensemble explored by molecular dynamics simulation

Lindsay, Richard J.; Mansbach, Rachael A.; Gnanakaran, S.; Shen, Tongye

doi:10.1016/j.bpc.2021.106552

Cited by 23 publications

(20 citation statements)

References 73 publications

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“…The change in contact frequency and extent of compaction for each segment is directly proportional to the change in NCPR values (0.03, 0.7, and 0.16 for N-ter, E-region, and C-ter, respectively) due to the switch in pH conditions from neutral to acidic. 56–58 We conclude that lowering pH modulates the contact probability 59–61 significantly in the E-region and hypothesize that this sequence with altered charges is probably conducive to secondary structure formation.…”

Section: Protα Compacts In the E-region (E41 - D80) At Low Phmentioning

confidence: 75%

“…On reducing pH, the electrostatic attraction between the oppositely charged residues present in both N-ter and C-ter vanishes, and the repulsion among the positively charged residues increases, which leads to a lowering in contact frequency (Figure 2A,C,D). In contrast, there is a strong repulsion between the negatively charged residues present in the E-region at neutral pH, which diminishes at low pH due to charge neutralization 56 (Figure 2A,C,D).…”

Section: åmentioning

confidence: 99%

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pH Induced Switch in the Conformational Ensemble of an Intrinsically Disordered Protein Prothymosin-αand Its Implications to Amyloid Fibril Formation

Baidya

Reddy

2022

Preprint

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Aggregation of intrinsically disordered proteins (IDPs) is the cause of various neu-rodegenerative diseases. Changes in solution pH can trigger IDP aggregation due to a shift in the IDP monomer population with a high aggregation propensity. Al-though there is experimental evidence that acidic pH promotes the compaction of IDP monomers, which subsequently leads to aggregation, the general mechanism is not clear. Using the IDP prothymosin-α(proTα), which is involved in multiple essential functions as a model system, we studied the pH effect on the conformational ensemble of proTαand probed its role in aggregation using a coarse-grained IDP model and molecular dynamics simulations. We show that compaction in the proTαdimension at low pH is due to the protein’s collapse in the intermediate region (E41 - D80) rich in glutamic acid residues. Further, theβ-sheet content increases in this region upon pH change from neutral to acidic. We hypothesized that the conformations with highβ-sheet content could act as aggregation-prone (N∗) states and nucleate the aggregation process. We validated our hypothesis by performing dimer simulations starting fromN∗and non-N∗states. We show that simulations initiated usingN∗states as initial conformations form dimers within 1.5μs, whereas the non-N∗states do not form dimers within this timescale. This study contributes to understanding the general principles of pH-induced IDP aggregation. The main result upon pH change from neutral to acidic, the intermediate region of proTαis responsible for aggregation due to an increase in itsβ-sheet forming propensity and forms the fibril core can be verified by experiments.Graphical TOC Entry

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Section: Protα Compacts In the E-region (E41 - D80) At Low Phmentioning

confidence: 75%

Section: åmentioning

confidence: 99%

pH Induced Switch in the Conformational Ensemble of an Intrinsically Disordered Protein Prothymosin-αand Its Implications to Amyloid Fibril Formation

Baidya

Reddy

2022

Preprint

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“…For protein-ligand interactions, we used an I-PCA style of contact statistical analysis ( Lindsay et al, 2018 ). The I-PCA method was initially developed to reveal internal domain structures of semi-structured biopolymers, from large-scale chromosome structures to intrinsically disordered proteins ( Das et al, 2020 ; Lindsay et al, 2021 ). In those cases, each row (or column) of the mean contact map of the structure ensemble is treated as a linear set of contact variables (the number of rows is the number of monomer units of the system) that symbolize the contact interaction with other unlabeled monomers.…”

Section: Discussionmentioning

confidence: 99%

Statistical Analysis of Protein-Ligand Interaction Patterns in Nuclear Receptor RORγ

Pham

Cheng²,

López³

et al. 2022

Front. Mol. Biosci.

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The receptor RORγ belongs to the nuclear receptor superfamily that senses small signaling molecules and regulates at the gene transcription level. Since RORγ has a high basal activity and plays an important role in immune responses, inhibitors targeting this receptor have been a focus for many studies. The receptor-ligand interaction is complex, and often subtle differences in ligand structure can determine its role as an inverse agonist or an agonist. We examined more than 130 existing RORγ crystal structures that have the same receptor complexed with different ligands. We reported the features of receptor-ligand interaction patterns and the differences between agonist and inverse agonist binding. Specific changes in the contact interaction map are identified to distinguish active and inactive conformations. Further statistical analysis of the contact interaction patterns using principal component analysis reveals a dominant mode which separates allosteric binding vs. canonical binding and a second mode which may indicate active vs. inactive structures. We also studied the nature of constitutive activity by performing a 100-ns computer simulation of apo RORγ. Using constitutively active nuclear receptor CAR as a comparison, we identified a group of conserved contacts that have similar contact strength between the two receptors. These conserved contact interactions, especially a couple key contacts in H11–H12 interaction, can be considered essential to the constitutive activity of RORγ. These protein-ligand and internal protein contact interactions can be useful in the development of new drugs that direct receptor activity.

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“…Hydrogen bonds can maintain the stability of the protein structure. More hydrogen bonds represent that the protein has a more stable structure [36]. The change in the secondary structure will inevitably lead to the change in hydrogen bond content, so the degree of conformation change the number of hydrogen bonds [29][30][31].…”

Section: Hydrogen Bonds Analysismentioning

confidence: 99%

Conformational Dynamics of Glucagon-like Peptide-2 with Different Electric Field

Sun

Wang

et al. 2022

Polymers

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Molecular dynamics (MD) simulation was used to study the influence of electric field on Glucagon-like Peptide-2 (GLP-2). Different electric field strengths (0 V/nm ≤ E ≤ 1 V/nm) were mainly carried out on GLP-2. The structural changes in GLP-2 were analyzed by the Root Mean Square Deviation (RMSD), Root Mean Square Fluctuation (RMSF), Radius of Gyration (Rg), Solvent Accessible Surface Area (SASA), Secondary Structure and the number of hydrogen bonds. The stable α—helix structure of GLP-2 was unwound and transformed into an unstable Turn and Coil structure since the stability of the GLP-2 protein structure was reduced under the electric field. Our results show that the degree of unwinding of the GLP-2 structure was not linearly related to the electric field intensity. E = 0.5 V/nm was a special point where the degree of unwinding of the GLP-2 structure reached the maximum at this electric field strength. Under a weak electric field, E < 0.5 V/nm, the secondary structure of GLP-2 becomes loose, and the entropy of the chain increases. When E reaches a certain value (E > 0.5 V/nm), the electric force of the charged residues reaches equilibrium, along the z-direction. Considering the confinement of moving along another direction, the residue is less free. Thus, entropy decreases and enthalpy increases, which enhance the interaction of adjacent residues. It is of benefit to recover hydrogen bonds in the middle region of the protein. These investigations, about the effect of an electric field on the structure of GLP-2, can provide some theoretical basis for the biological function of GLP-2 in vivo.

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Effects of pH on an IDP conformational ensemble explored by molecular dynamics simulation

Cited by 23 publications

References 73 publications

pH Induced Switch in the Conformational Ensemble of an Intrinsically Disordered Protein Prothymosin-αand Its Implications to Amyloid Fibril Formation

pH Induced Switch in the Conformational Ensemble of an Intrinsically Disordered Protein Prothymosin-αand Its Implications to Amyloid Fibril Formation

Statistical Analysis of Protein-Ligand Interaction Patterns in Nuclear Receptor RORγ

Conformational Dynamics of Glucagon-like Peptide-2 with Different Electric Field

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