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Molecular Dynamics Simulations and Structural Analysis of Protein Domains

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

Deadline for manuscript submissions: closed (31 March 2024) | Viewed by 7097

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Guest Editor
Department of Biological Research on the Red Blood Cells, INTS, INSERM UMR_S 1134, Université de Paris, Université de la Réunion, 75739 Paris, France
Interests: structural bioinformatics; bioinformatics; next-generation sequence; drug design; deep learning
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Special Issue Information

Dear Colleagues,

The 3D structure of proteins is the basis for all their biological functions. For more than 50 years, obtaining this structure has been difficult, costly and sometimes impossible. Molecular modelling approaches are therefore making it possible to increase our knowledge by providing high-quality 3D structural models. In this context, the AlphaFold2 deep learning approach has enabled significant progress, with hundreds of millions of 3D structural models being made available to the scientific community.

However, the 3D structure gives only a small insight into biological function. The 3D structure or 3D model is static, whereas the different parts of proteins are rigid, flexible, highly flexible or even completely disordered. Similarly, biological function can be associated with major conformational changes that are not provided by knowledge of a single structure. It is therefore essential to understand the life of protein structures through their dynamics. Molecular dynamics simulations (DMs), both classical and advanced, provide access to much more detailed questions of critical biomedical interest. For example, a point mutation in a structural model does not explain the functional change at the atomic level. Molecular dynamics simulations are needed to generate hypotheses about the effects of these variants. In this way, DMs allow us to see allosteric changes that are sometimes impossible to characterise experimentally.

This Special Issue will therefore focus on issues ranging from the most fundamental to the most applied research on protein structures (or structural models), through the use and/or development of both classical and more innovative simulations. It can start with the construction of a model or the use of a 3D structure and then its analysis by DMs, the comparison between different variants, the question of the binding of ligands or proteins of interest, etc.

Prof. Dr. Alexandre G. De Brevern
Guest Editor

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Keywords

  • protein structures
  • molecular dynamics
  • advanced molecular dynamics
  • variants
  • pathologies
  • drug design
  • allostery
  • protein domains
  • secondary structures
  • methodological development
  • protein design
  • ligands
  • normal mode analysis
  • machine learning

Published Papers (7 papers)

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Research

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22 pages, 3567 KiB  
Article
Highlighting the Major Role of Cyclin C in Cyclin-Dependent Kinase 8 Activity through Molecular Dynamics Simulations
by Sonia Ziada, Julien Diharce, Dylan Serillon, Pascal Bonnet and Samia Aci-Sèche
Int. J. Mol. Sci. 2024, 25(10), 5411; https://doi.org/10.3390/ijms25105411 - 15 May 2024
Viewed by 252
Abstract
Dysregulation of cyclin-dependent kinase 8 (CDK8) activity has been associated with many diseases, including colorectal and breast cancer. As usual in the CDK family, the activity of CDK8 is controlled by a regulatory protein called cyclin C (CycC). But, while human CDK family [...] Read more.
Dysregulation of cyclin-dependent kinase 8 (CDK8) activity has been associated with many diseases, including colorectal and breast cancer. As usual in the CDK family, the activity of CDK8 is controlled by a regulatory protein called cyclin C (CycC). But, while human CDK family members are generally activated in two steps, that is, the binding of the cyclin to CDK and the phosphorylation of a residue in the CDK activation loop, CDK8 does not require the phosphorylation step to be active. Another peculiarity of CDK8 is its ability to be associated with CycC while adopting an inactive form. These specificities raise the question of the role of CycC in the complex CDK8–CycC, which appears to be more complex than the other members of the CDK family. Through molecular dynamics (MD) simulations and binding free energy calculations, we investigated the effect of CycC on the structure and dynamics of CDK8. In a second step, we particularly focused our investigation on the structural and molecular basis of the protein–protein interaction between the two partners by finely analyzing the energetic contribution of residues and simulating the transition between the active and the inactive form. We found that CycC has a stabilizing effect on CDK8, and we identified specific interaction hotspots within its interaction surface compared to other human CDK/Cyc pairs. Targeting these specific interaction hotspots could be a promising approach in terms of specificity to effectively disrupt the interaction between CDK8. The simulation of the conformational transition from the inactive to the active form of CDK8 suggests that the residue Glu99 of CycC is involved in the orientation of three conserved arginines of CDK8. Thus, this residue may assume the role of the missing phosphorylation step in the activation mechanism of CDK8. In a more general view, these results point to the importance of keeping the CycC in computational studies when studying the human CDK8 protein in both the active and the inactive form. Full article
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19 pages, 2741 KiB  
Article
Conformational Space of the Translocation Domain of Botulinum Toxin: Atomistic Modeling and Mesoscopic Description of the Coiled-Coil Helix Bundle
by Alexandre Delort, Grazia Cottone, Thérèse E. Malliavin and Martin Michael Müller
Int. J. Mol. Sci. 2024, 25(5), 2481; https://doi.org/10.3390/ijms25052481 - 20 Feb 2024
Viewed by 639
Abstract
The toxicity of botulinum multi-domain neurotoxins (BoNTs) arises from a sequence of molecular events, in which the translocation of the catalytic domain through the membrane of a neurotransmitter vesicle plays a key role. A recent structural study of the translocation domain of BoNTs [...] Read more.
The toxicity of botulinum multi-domain neurotoxins (BoNTs) arises from a sequence of molecular events, in which the translocation of the catalytic domain through the membrane of a neurotransmitter vesicle plays a key role. A recent structural study of the translocation domain of BoNTs suggests that the interaction with the membrane is driven by the transition of an α helical switch towards a β hairpin. Atomistic simulations in conjunction with the mesoscopic Twister model are used to investigate the consequences of this proposition for the toxin–membrane interaction. The conformational mobilities of the domain, as well as the effect of the membrane, implicitly examined by comparing water and water–ethanol solvents, lead to the conclusion that the transition of the switch modifies the internal dynamics and the effect of membrane hydrophobicity on the whole protein. The central two α helices, helix 1 and helix 2, forming two coiled-coil motifs, are analyzed using the Twister model, in which the initial deformation of the membrane by the protein is caused by the presence of local torques arising from asymmetric positions of hydrophobic residues. Different torque distributions are observed depending on the switch conformations and permit an origin for the mechanism opening the membrane to be proposed. Full article
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26 pages, 7267 KiB  
Article
Synergy of Mutation-Induced Effects in Human Vitamin K Epoxide Reductase: Perspectives and Challenges for Allo-Network Modulator Design
by Marina Botnari and Luba Tchertanov
Int. J. Mol. Sci. 2024, 25(4), 2043; https://doi.org/10.3390/ijms25042043 - 7 Feb 2024
Cited by 1 | Viewed by 652
Abstract
The human Vitamin K Epoxide Reductase Complex (hVKORC1), a key enzyme transforming vitamin K into the form necessary for blood clotting, requires for its activation the reducing equivalents delivered by its redox partner through thiol-disulfide exchange reactions. The luminal loop (L-loop) is the [...] Read more.
The human Vitamin K Epoxide Reductase Complex (hVKORC1), a key enzyme transforming vitamin K into the form necessary for blood clotting, requires for its activation the reducing equivalents delivered by its redox partner through thiol-disulfide exchange reactions. The luminal loop (L-loop) is the principal mediator of hVKORC1 activation, and it is a region frequently harbouring numerous missense mutations. Four L-loop hVKORC1 mutants, suggested in vitro as either resistant (A41S, H68Y) or completely inactive (S52W, W59R), were studied in the oxidised state by numerical approaches (in silico). The DYNASOME and POCKETOME of each mutant were characterised and compared to the native protein, recently described as a modular protein composed of the structurally stable transmembrane domain (TMD) and the intrinsically disordered L-loop, exhibiting quasi-independent dynamics. The DYNASOME of mutants revealed that L-loop missense point mutations impact not only its folding and dynamics, but also those of the TMD, highlighting a strong mutation-specific interdependence between these domains. Another consequence of the mutation-induced effects manifests in the global changes (geometric, topological, and probabilistic) of the newly detected cryptic pockets and the alternation of the recognition properties of the L-loop with its redox protein. Based on our results, we postulate that (i) intra-protein allosteric regulation and (ii) the inherent allosteric regulation and cryptic pockets of each mutant depend on its DYNASOME; and (iii) the recognition of the redox protein by hVKORC1 (INTERACTOME) depend on their DYNASOME. This multifaceted description of proteins produces “omics” data sets, crucial for understanding the physiological processes of proteins and the pathologies caused by alteration of the protein properties at various “omics” levels. Additionally, such characterisation opens novel perspectives for the development of “allo-network drugs” essential for the treatment of blood disorders. Full article
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14 pages, 8235 KiB  
Article
Classification of MLH1 Missense VUS Using Protein Structure-Based Deep Learning-Ramachandran Plot-Molecular Dynamics Simulations Method
by Benjamin Tam, Zixin Qin, Bojin Zhao, Siddharth Sinha, Chon Lok Lei and San Ming Wang
Int. J. Mol. Sci. 2024, 25(2), 850; https://doi.org/10.3390/ijms25020850 - 10 Jan 2024
Viewed by 1151
Abstract
Pathogenic variation in DNA mismatch repair (MMR) gene MLH1 is associated with Lynch syndrome (LS), an autosomal dominant hereditary cancer. Of the 3798 MLH1 germline variants collected in the ClinVar database, 38.7% (1469) were missense variants, of which 81.6% (1199) were classified as [...] Read more.
Pathogenic variation in DNA mismatch repair (MMR) gene MLH1 is associated with Lynch syndrome (LS), an autosomal dominant hereditary cancer. Of the 3798 MLH1 germline variants collected in the ClinVar database, 38.7% (1469) were missense variants, of which 81.6% (1199) were classified as Variants of Uncertain Significance (VUS) due to the lack of functional evidence. Further determination of the impact of VUS on MLH1 function is important for the VUS carriers to take preventive action. We recently developed a protein structure-based method named “Deep Learning-Ramachandran Plot-Molecular Dynamics Simulation (DL-RP-MDS)” to evaluate the deleteriousness of MLH1 missense VUS. The method extracts protein structural information by using the Ramachandran plot-molecular dynamics simulation (RP-MDS) method, then combines the variation data with an unsupervised learning model composed of auto-encoder and neural network classifier to identify the variants causing significant change in protein structure. In this report, we applied the method to classify 447 MLH1 missense VUS. We predicted 126/447 (28.2%) MLH1 missense VUS were deleterious. Our study demonstrates that DL-RP-MDS is able to classify the missense VUS based solely on their impact on protein structure. Full article
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19 pages, 10102 KiB  
Article
A Proposal for a Consolidated Structural Model of the CagY Protein of Helicobacter pylori
by Mario Angel López-Luis, Eva Elda Soriano-Pérez, José Carlos Parada-Fabián, Javier Torres, Rogelio Maldonado-Rodríguez and Alfonso Méndez-Tenorio
Int. J. Mol. Sci. 2023, 24(23), 16781; https://doi.org/10.3390/ijms242316781 - 26 Nov 2023
Viewed by 1160
Abstract
CagY is the largest and most complex protein from Helicobacter pylori’s (Hp) type IV secretion system (T4SS), playing a critical role in the modulation of gastric inflammation and risk for gastric cancer. CagY spans from the inner to the outer membrane, forming a [...] Read more.
CagY is the largest and most complex protein from Helicobacter pylori’s (Hp) type IV secretion system (T4SS), playing a critical role in the modulation of gastric inflammation and risk for gastric cancer. CagY spans from the inner to the outer membrane, forming a channel through which Hp molecules are injected into human gastric cells. Yet, a tridimensional structure has been reported for only short segments of the protein. This intricate protein was modeled using different approaches, including homology modeling, ab initio, and deep learning techniques. The challengingly long middle repeat region (MRR) was modeled using deep learning and optimized using equilibrium molecular dynamics. The previously modeled segments were assembled into a 1595 aa chain and a 14-chain CagY multimer structure was assembled by structural alignment. The final structure correlated with published structures and allowed to show how the multimer may form the T4SS channel through which CagA and other molecules are translocated to gastric cells. The model confirmed that MRR, the most polymorphic and complex region of CagY, presents numerous cysteine residues forming disulfide bonds that stabilize the protein and suggest this domain may function as a contractile region playing an essential role in the modulating activity of CagY on tissue inflammation. Full article
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Review

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43 pages, 3284 KiB  
Review
An Update on Protein Kinases as Therapeutic Targets—Part I: Protein Kinase C Activation and Its Role in Cancer and Cardiovascular Diseases
by Shmuel Silnitsky, Samuel J. S. Rubin, Mulate Zerihun and Nir Qvit
Int. J. Mol. Sci. 2023, 24(24), 17600; https://doi.org/10.3390/ijms242417600 - 18 Dec 2023
Cited by 3 | Viewed by 1846
Abstract
Protein kinases are one of the most significant drug targets in the human proteome, historically harnessed for the treatment of cancer, cardiovascular disease, and a growing number of other conditions, including autoimmune and inflammatory processes. Since the approval of the first kinase inhibitors [...] Read more.
Protein kinases are one of the most significant drug targets in the human proteome, historically harnessed for the treatment of cancer, cardiovascular disease, and a growing number of other conditions, including autoimmune and inflammatory processes. Since the approval of the first kinase inhibitors in the late 1990s and early 2000s, the field has grown exponentially, comprising 98 approved therapeutics to date, 37 of which were approved between 2016 and 2021. While many of these small-molecule protein kinase inhibitors that interact orthosterically with the protein kinase ATP binding pocket have been massively successful for oncological indications, their poor selectively for protein kinase isozymes have limited them due to toxicities in their application to other disease spaces. Thus, recent attention has turned to the use of alternative allosteric binding mechanisms and improved drug platforms such as modified peptides to design protein kinase modulators with enhanced selectivity and other pharmacological properties. Herein we review the role of different protein kinase C (PKC) isoforms in cancer and cardiovascular disease, with particular attention to PKC-family inhibitors. We discuss translational examples and carefully consider the advantages and limitations of each compound (Part I). We also discuss the recent advances in the field of protein kinase modulators, leverage molecular docking to model inhibitor–kinase interactions, and propose mechanisms of action that will aid in the design of next-generation protein kinase modulators (Part II). Full article
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26 pages, 3214 KiB  
Review
An Update on Protein Kinases as Therapeutic Targets—Part II: Peptides as Allosteric Protein Kinase C Modulators Targeting Protein–Protein Interactions
by Mulate Zerihun, Samuel J. S. Rubin, Shmuel Silnitsky and Nir Qvit
Int. J. Mol. Sci. 2023, 24(24), 17504; https://doi.org/10.3390/ijms242417504 - 15 Dec 2023
Viewed by 925
Abstract
Human protein kinases are highly-sought-after drug targets, historically harnessed for treating cancer, cardiovascular disease, and an increasing number of autoimmune and inflammatory conditions. Most current treatments involve small molecule protein kinase inhibitors that interact orthosterically with the protein kinase ATP-binding pocket. As a [...] Read more.
Human protein kinases are highly-sought-after drug targets, historically harnessed for treating cancer, cardiovascular disease, and an increasing number of autoimmune and inflammatory conditions. Most current treatments involve small molecule protein kinase inhibitors that interact orthosterically with the protein kinase ATP-binding pocket. As a result, these compounds are often poorly selective and highly toxic. Part I of this series reviews the role of PKC isoforms in various human diseases, featuring cancer and cardiovascular disease, as well as translational examples of PKC modulation applied to human health and disease. In the present Part II, we discuss alternative allosteric binding mechanisms for targeting PKC, as well as novel drug platforms, such as modified peptides. A major goal is to design protein kinase modulators with enhanced selectivity and improved pharmacological properties. To this end, we use molecular docking analysis to predict the mechanisms of action for inhibitor–kinase interactions that can facilitate the development of next-generation PKC modulators. Full article
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