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Dynamic and Structural Aspects of Protein Function and Allostery
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Dynamic and Structural Aspects of Protein Function and Allostery

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Biophysics".

Deadline for manuscript submissions: closed (20 January 2023) | Viewed by 9811

Special Issue Editors

Dr. Xiakun Chu

E-Mail Website
Guest Editor
Department of Chemistry, Stony Brook University, 100 Nicolls Road, 104 Chemistry, Stony Brook, NY, USA
Interests: protein folding; intrinsically disordered proteins; protein binding; protein-DNA recognition; chromosome dynamics; genome structure; energy landscape; coarse-grained model
Dr. Yong Wang

E-Mail Website
Guest Editor
Shanghai Institute for Advanced Study, Institute of Quantitative Biology, College of Life Sciences, Zhejiang University, Hangzhou 310027, China
Interests: multiscale modelling; enhanced sampling; protein folding; membrane transporter; free energy calculation; integrative structural modelling; coupled folding and binding of IDP; protein structural refinement; protein structure prediction
Dr. Lintai Da

E-Mail Website
Guest Editor
Key Laboratory of Systems Biomedicine (Ministry of Education), Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, Shanghai 200240, China
Interests: protein conformational dynamics; protein-DNA interaction; Markov state model; protein engineering; structural-based drug discovery

Special Issue Information

Dear Colleagues,

Proteins are the most fundamental nano-bio-machines that participate in a wide variety of pivotal cellular activities. Protein exerts its biological function through its specific 3D structure. Increasing evidence has suggested that proteins often undergo allosteric changes when realizing the functional purpose. The conformational dynamics of proteins, either in response to the binding of other molecules or in forms of an intrinsic property, play vital roles in the intricate biological processes. Despite the well-recognized importance of structure and dynamics for protein function, the link from the sequence information to the structural architecture and conformational motions, and finally to the biological function remains poorly understood.

This Special Issue aims to provide a forum for the publications on unraveling the mysterious relationship of the “structure-dynamics-function” in proteins. We welcome different types of papers, including research articles, communications/letters, reviews, etc., focusing on employing different techniques from different aspects of theories, simulations and experiments, to study protein structure and dynamics in relation to the biological function.

Dr. Xiakun Chu
Dr. Yong Wang
Dr. Lintai Da
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

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Keywords

  • protein dynamics and allostery
  • protein folding
  • intrinsically disordered protein
  • molecular modeling and simulation
  • protein design and engineering
  • integrative structural biology
  • free energy calculation
  • enhanced sampling methods
  • Markov state model
  • protein-protein interactions

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Published Papers (4 papers)

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Research

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14 pages, 5279 KiB  
Article
Automated Path Searching Reveals the Mechanism of Hydrolysis Enhancement by T4 Lysozyme Mutants
by Kun Xi and Lizhe Zhu
Int. J. Mol. Sci. 2022, 23(23), 14628; https://doi.org/10.3390/ijms232314628 - 23 Nov 2022
Cited by 4 | Viewed by 1881
Abstract
Bacteriophage T4 lysozyme (T4L) is a glycosidase that is widely applied as a natural antimicrobial agent in the food industry. Due to its wide applications and small size, T4L has been regarded as a model system for understanding protein dynamics and for large-scale [...] Read more.
Bacteriophage T4 lysozyme (T4L) is a glycosidase that is widely applied as a natural antimicrobial agent in the food industry. Due to its wide applications and small size, T4L has been regarded as a model system for understanding protein dynamics and for large-scale protein engineering. Through structural insights from the single conformation of T4L, a series of mutations (L99A,G113A,R119P) have been introduced, which have successfully raised the fractional population of its only hydrolysis-competent excited state to 96%. However, the actual impact of these substitutions on its dynamics remains unclear, largely due to the lack of highly efficient sampling algorithms. Here, using our recently developed travelling-salesman-based automated path searching (TAPS), we located the minimum-free-energy path (MFEP) for the transition of three T4L mutants from their ground states to their excited states. All three mutants share a three-step transition: the flipping of F114, the rearrangement of α0/α1 helices, and final refinement. Remarkably, the MFEP revealed that the effects of the mutations are drastically beyond the expectations of their original design: (a) the G113A substitution not only enhances helicity but also fills the hydrophobic Cavity I and reduces the free energy barrier for flipping F114; (b) R119P barely changes the stability of the ground state but stabilizes the excited state through rarely reported polar contacts S117OG:N132ND2, E11OE1:R145NH1, and E11OE2:Q105NE2; (c) the residue W138 flips into Cavity I and further stabilizes the excited state for the triple mutant L99A,G113A,R119P. These novel insights that were unexpected in the original mutant design indicated the necessity of incorporating path searching into the workflow of rational protein engineering. Full article
(This article belongs to the Special Issue Dynamic and Structural Aspects of Protein Function and Allostery)
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14 pages, 3814 KiB  
Article
Deciphering the Effect of Lysine Acetylation on the Misfolding and Aggregation of Human Tau Fragment 171IPAKTPPAPK180 Using Molecular Dynamic Simulation and the Markov State Model
by Syed Jawad Ali Shah, Haiyang Zhong, Qianqian Zhang and Huanxiang Liu
Int. J. Mol. Sci. 2022, 23(5), 2399; https://doi.org/10.3390/ijms23052399 - 22 Feb 2022
Cited by 5 | Viewed by 2544
Abstract
The formation of neurofibrillary tangles (NFT) with β-sheet-rich structure caused by abnormal aggregation of misfolded microtubule-associated protein Tau is a hallmark of tauopathies, including Alzheimer’s Disease. It has been reported that acetylation, especially K174 located in the proline-rich region, can largely promote Tau [...] Read more.
The formation of neurofibrillary tangles (NFT) with β-sheet-rich structure caused by abnormal aggregation of misfolded microtubule-associated protein Tau is a hallmark of tauopathies, including Alzheimer’s Disease. It has been reported that acetylation, especially K174 located in the proline-rich region, can largely promote Tau aggregation. So far, the mechanism of the abnormal acetylation of Tau that affects its misfolding and aggregation is still unclear. Therefore, revealing the effect of acetylation on Tau aggregation could help elucidate the pathogenic mechanism of tauopathies. In this study, molecular dynamics simulation combined with multiple computational analytical methods were performed to reveal the effect of K174 acetylation on the spontaneous aggregation of Tau peptide 171IPAKTPPAPK180, and the dimerization mechanism as an early stage of the spontaneous aggregation was further specifically analyzed by Markov state model (MSM) analysis. The results showed that both the actual acetylation and the mutation mimicking the acetylated state at K174 induced the aggregation of the studied Tau fragment; however, the effect of actual acetylation on the aggregation was more pronounced. In addition, acetylated K174 plays a major contributing role in forming and stabilizing the antiparallel β-sheet dimer by forming several hydrogen bonds and side chain van der Waals interactions with residues I171, P172, A173 and T175 of the corresponding chain. In brief, this study uncovered the underlying mechanism of Tau peptide aggregation in response to the lysine K174 acetylation, which can deepen our understanding on the pathogenesis of tauopathies. Full article
(This article belongs to the Special Issue Dynamic and Structural Aspects of Protein Function and Allostery)
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13 pages, 6083 KiB  
Article
Computational Study on E-Hooks of Tubulins in the Binding Process with Kinesin
by Yixin Xie and Lin Li
Int. J. Mol. Sci. 2022, 23(4), 2035; https://doi.org/10.3390/ijms23042035 - 12 Feb 2022
Cited by 2 | Viewed by 1798
Abstract
Cargo transport within cells is essential to healthy cells, which requires microtubules-based motors, including kinesin. The C-terminal tails (E-hooks) of alpha and beta tubulins of microtubules have been proven to play important roles in interactions between the kinesins and tubulins. Here, we implemented [...] Read more.
Cargo transport within cells is essential to healthy cells, which requires microtubules-based motors, including kinesin. The C-terminal tails (E-hooks) of alpha and beta tubulins of microtubules have been proven to play important roles in interactions between the kinesins and tubulins. Here, we implemented multi-scale computational methods in E-hook-related analyses, including flexibility investigations of E-hooks, binding force calculations at binding interfaces between kinesin and tubulins, electrostatic potential calculations on the surface of kinesin and tubulins. Our results show that E-hooks have several functions during the binding process: E-hooks utilize their own high flexibilities to increase the chances of reaching a kinesin; E-hooks help tubulins to be more attractive to kinesin. Besides, we also observed the differences between alpha and beta tubulins: beta tubulin shows a higher flexibility than alpha tubulin; beta tubulin generates stronger attractive forces (about twice the strengths) to kinesin at different distances, no matter with E-hooks in the structure or not. Those facts may indicate that compared to alpha tubulin, beta tubulin contributes more to attracting and catching a kinesin to microtubule. Overall, this work sheds the light on microtubule studies, which will also benefit the treatments of neurodegenerative diseases, cancer treatments, and preventions in the future. Full article
(This article belongs to the Special Issue Dynamic and Structural Aspects of Protein Function and Allostery)
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Review

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15 pages, 4531 KiB  
Review
Allosterism in the PDZ Family
by Amy O. Stevens and Yi He
Int. J. Mol. Sci. 2022, 23(3), 1454; https://doi.org/10.3390/ijms23031454 - 27 Jan 2022
Cited by 7 | Viewed by 2741
Abstract
Dynamic allosterism allows the propagation of signal throughout a protein. The PDZ (PSD-95/Dlg1/ZO-1) family has been named as a classic example of dynamic allostery in small modular domains. While the PDZ family consists of more than 200 domains, previous efforts have primarily focused [...] Read more.
Dynamic allosterism allows the propagation of signal throughout a protein. The PDZ (PSD-95/Dlg1/ZO-1) family has been named as a classic example of dynamic allostery in small modular domains. While the PDZ family consists of more than 200 domains, previous efforts have primarily focused on a few well-studied PDZ domains, including PTP-BL PDZ2, PSD-95 PDZ3, and Par6 PDZ. Taken together, experimental and computational studies have identified regions of these domains that are dynamically coupled to ligand binding. These regions include the αA helix, the αB lower-loop, and the αC helix. In this review, we summarize the specific residues on the αA helix, the αB lower-loop, and the αC helix of PTP-BL PDZ2, PSD-95 PDZ3, and Par6 PDZ that have been identified as participants in dynamic allostery by either experimental or computational approaches. This review can serve as an index for researchers to look back on the previously identified allostery in the PDZ family. Interestingly, our summary of previous work reveals clear consistencies between the domains. While the PDZ family has a low sequence identity, we show that some of the most consistently identified allosteric residues within PTP-BL PDZ2 and PSD-95 PDZ3 domains are evolutionarily conserved. These residues include A46/A347, V61/V362, and L66/L367 on PTP-BL PDZ2 and PSD-95 PDZ3, respectively. Finally, we expose a need for future work to explore dynamic allostery within (1) PDZ domains with multiple binding partners and (2) multidomain constructs containing a PDZ domain. Full article
(This article belongs to the Special Issue Dynamic and Structural Aspects of Protein Function and Allostery)
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