scholarly journals Variance of Atomic Coordinates as a Dynamical Metric to Distinguish Proteins and Protein-Protein Interactions in Molecular Dynamics Simulations

2020 ◽  
Author(s):  
Sanjoy Paul ◽  
Sri Rama Koti Ainavarapu ◽  
Ravindra Venkatramani
Keyword(s):  
Protein Interactions ◽  
Structural Changes ◽  
Md Simulations ◽  
Comparative Assessment ◽  
Protein Protein Interactions ◽  
Multiple Protein ◽  
Functional Consequences ◽  
Global Equilibrium ◽  
Dynamics Simulations ◽  
Atomic Coordinates

<b><i>In this manuscript, </i>we introduce the Cumulative Variance of Coordinate Fluctuations (CVCF) along atomistic MD trajectories, as a dynamical metric to examine protein dynamics and sampling convergence in MD simulations.</b> Using model 1D and 2D PES, we first show that CVCF, which traces over the fluctuations of protein atoms as a function of sampling coordinate (time in MD simulations), captures both local and global equilibria to distinguish the underlying PES of proteins. For both model PES and protein trajectories, we compare the information content present in CVCF traces with that obtained using other measures proposed in literature to reveal conditions under which a consistent interpretation of data can be obtained. <b>Importantly, we show that independent of convergence to either local or global equilibrium, the values and features of protein CVCF can provide a comparative assessment of the ruggedness and curvature of the underlying PES sampled by proteins along MD trajectories.</b> Trends in CVCF therefore enable us to compare features of the PES across multiple protein systems using MD simulations. We demonstrate some of the attractive features of a CVCF based analysis on multi-microsecond (ms) MD trajectories of structurally homologous ubiquitin family proteins which present a particularly striking example in nature wherein sequence changes and complexation which do not lead to prominent structural changes bring about dramatic functional consequences.

scholarly journals Variance of Atomic Coordinates as a Dynamical Metric to Distinguish Proteins and Protein-Protein Interactions in Molecular Dynamics Simulations

2020 ◽  
Author(s):  
Sanjoy Paul ◽  
Sri Rama Koti Ainavarapu ◽  
Ravindra Venkatramani
Keyword(s):  
Protein Interactions ◽  
Structural Changes ◽  
Md Simulations ◽  
Comparative Assessment ◽  
Protein Protein Interactions ◽  
Multiple Protein ◽  
Functional Consequences ◽  
Global Equilibrium ◽  
Dynamics Simulations ◽  
Atomic Coordinates

<b><i>In this manuscript, </i>we introduce the Cumulative Variance of Coordinate Fluctuations (CVCF) along atomistic MD trajectories, as a dynamical metric to examine protein dynamics and sampling convergence in MD simulations.</b> Using model 1D and 2D PES, we first show that CVCF, which traces over the fluctuations of protein atoms as a function of sampling coordinate (time in MD simulations), captures both local and global equilibria to distinguish the underlying PES of proteins. For both model PES and protein trajectories, we compare the information content present in CVCF traces with that obtained using other measures proposed in literature to reveal conditions under which a consistent interpretation of data can be obtained. <b>Importantly, we show that independent of convergence to either local or global equilibrium, the values and features of protein CVCF can provide a comparative assessment of the ruggedness and curvature of the underlying PES sampled by proteins along MD trajectories.</b> Trends in CVCF therefore enable us to compare features of the PES across multiple protein systems using MD simulations. We demonstrate some of the attractive features of a CVCF based analysis on multi-microsecond (ms) MD trajectories of structurally homologous ubiquitin family proteins which present a particularly striking example in nature wherein sequence changes and complexation which do not lead to prominent structural changes bring about dramatic functional consequences.

scholarly journals Impact of Reactive Oxygen and Nitrogen Species Produced by Plasma on Mdm2–p53 Complex

2021 ◽  
Vol 22 (17) ◽  
pp. 9585
Author(s):  
Pankaj Attri ◽  
Hirofumi Kurita ◽  
Kazunori Koga ◽  
Masaharu Shiratani
Keyword(s):  
Tumor Suppressor ◽  
Protein Interactions ◽  
Structural Changes ◽  
Md Simulations ◽  
Tumor Suppressor Protein ◽  
Protein Protein Interactions ◽  
Tumor Suppressor Protein P53 ◽  
Protein P53 ◽  
Before And After ◽  
High Flexibility

The study of protein–protein interactions is of great interest. Several early studies focused on the murine double minute 2 (Mdm2)–tumor suppressor protein p53 interactions. However, the effect of plasma treatment on Mdm2 and p53 is still absent from the literature. This study investigated the structural changes in Mdm2, p53, and the Mdm2–p53 complex before and after possible plasma oxidation through molecular dynamic (MD) simulations. MD calculation revealed that the oxidized Mdm2 bounded or unbounded showed high flexibility that might increase the availability of tumor suppressor protein p53 in plasma-treated cells. This study provides insight into Mdm2 and p53 for a better understanding of plasma oncology.

The impact of water on the ambivalent behavior and paradoxical phenomenon of the amyloid-β fibril protein

2017 ◽  
Vol 8 (5-6) ◽  
pp. 213-220
Author(s):  
Tamás Vajda ◽  
András Perczel
Keyword(s):  
Protein Interactions ◽  
Crucial Role ◽  
Amyloid Β ◽  
Md Simulations ◽  
Protein Protein Interactions ◽  
Hindered Rotation ◽  
Dynamics Simulations ◽  
The Impact ◽  
Dimerization Process

AbstractThe crucial role of water in amyloid-β(Aβ) fibril proteins is evaluated in several ways including the water’s thermodynamic and kinetic solvation effects. As regards the water’s character, its hindered-rotation barriers are also considered. The following protein molecules considered here are: the Aβ40 (PDB ID: 2LMN), Aβ42 (PDB ID: 5KK3 and 2NAO) and the double-layered Aβ17−42 fibril. We discuss: (i) extracellular Aβ40 and Aβ42 fibril monomers exhibit an ambivalent propensity to transform into a helical form toward the N-term region and a β-strand-like form near the C-terminal; (ii) interfacial water molecules play a crucial role in protein-protein interactions, as molecular dynamics simulations have shown a significant impact on the protein-protein binding; (iii) it is shown that the spontaneous dimerization process of the Aβ42 fibril protein in water occurs via a two-step nucleation-accommodation mechanism; (iv) MD simulations of the double-layered Aβ17−42 fibril model show that the C↔C interface appears more energetically favorable than the N↔N interface due to large hydrophobic contacts; (v) the water’s role in the HET-s prion and in the Aβ fibrillar aggregates; (vi) it was found that the monomer-oligomer equilibrium spontaneously dissociates into stable monomeric species when they are incubated up to 3 μm for a longer time (>1 week) in a physiological buffer.

scholarly journals POT1-TPP1 differentially regulates telomerase via POT1 His266 and as a function of single-stranded telomere DNA length

2019 ◽  
Vol 116 (47) ◽  
pp. 23527-23533 ◽  
Author(s):  
Mengyuan Xu ◽  
Janna Kiselar ◽  
Tawna L. Whited ◽  
Wilnelly Hernandez-Sanchez ◽  
Derek J. Taylor
Keyword(s):  
Conformational Changes ◽  
Protein Interactions ◽  
Environmental Changes ◽  
Lymphocytic Leukemia ◽  
Protein Protein Interactions ◽  
Cellular Environment ◽  
Multiple Protein ◽  
Linear Chromosomes ◽  
Hydroxyl Radical Footprinting ◽  
Regulate Telomere Length

Telomeres cap the ends of linear chromosomes and terminate in a single-stranded DNA (ssDNA) overhang recognized by POT1-TPP1 heterodimers to help regulate telomere length homeostasis. Here hydroxyl radical footprinting coupled with mass spectrometry was employed to probe protein–protein interactions and conformational changes involved in the assembly of telomere ssDNA substrates of differing lengths bound by POT1-TPP1 heterodimers. Our data identified environmental changes surrounding residue histidine 266 of POT1 that were dependent on telomere ssDNA substrate length. We further determined that the chronic lymphocytic leukemia-associated H266L substitution significantly reduced POT1-TPP1 binding to short ssDNA substrates; however, it only moderately impaired the heterodimer binding to long ssDNA substrates containing multiple protein binding sites. Additionally, we identified a telomerase inhibitory role when several native POT1-TPP1 proteins coat physiologically relevant lengths of telomere ssDNA. This POT1-TPP1 complex-mediated inhibition of telomerase is abrogated in the context of the POT1 H266L mutation, which leads to telomere overextension in a malignant cellular environment.

scholarly journals Molecular dynamics shows complex interplay and long-range effects of post-translational modifications in yeast protein interactions

2021 ◽  
Vol 17 (5) ◽  
pp. e1008988
Author(s):  
Nikolina ŠoŠtarić ◽  
Vera van Noort
Keyword(s):  
Molecular Dynamics ◽  
Conformational Changes ◽  
Protein Interactions ◽  
Protein Structures ◽  
Cellular Protein ◽  
Free Energy Calculations ◽  
Protein Protein Interactions ◽  
Post Translational Modifications ◽  
Protein Properties ◽  
Dynamics Simulations

Post-translational modifications (PTMs) play a vital, yet often overlooked role in the living cells through modulation of protein properties, such as localization and affinity towards their interactors, thereby enabling quick adaptation to changing environmental conditions. We have previously benchmarked a computational framework for the prediction of PTMs’ effects on the stability of protein-protein interactions, which has molecular dynamics simulations followed by free energy calculations at its core. In the present work, we apply this framework to publicly available data on Saccharomyces cerevisiae protein structures and PTM sites, identified in both normal and stress conditions. We predict proteome-wide effects of acetylations and phosphorylations on protein-protein interactions and find that acetylations more frequently have locally stabilizing roles in protein interactions, while the opposite is true for phosphorylations. However, the overall impact of PTMs on protein-protein interactions is more complex than a simple sum of local changes caused by the introduction of PTMs and adds to our understanding of PTM cross-talk. We further use the obtained data to calculate the conformational changes brought about by PTMs. Finally, conservation of the analyzed PTM residues in orthologues shows that some predictions for yeast proteins will be mirrored to other organisms, including human. This work, therefore, contributes to our overall understanding of the modulation of the cellular protein interaction networks in yeast and beyond.

scholarly journals An integrative approach unveils a distal encounter site for rPTPε and phospho-Src complex formation

2021 ◽  
Author(s):  
Nadendla EswarKumar ◽  
Cheng-Han Yang ◽  
Sunilkumar Tewary ◽  
Yi-Qi Yeh ◽  
Hsiao-Ching Yang ◽  
...  
Keyword(s):  
Protein Interactions ◽  
Protein Complex ◽  
Tyrosine Phosphatase ◽  
Complex Structure ◽  
Protein Crystallography ◽  
Md Simulations ◽  
Integrative Approach ◽  
Single Mutation ◽  
Protein Protein Interactions ◽  
Transient Nature

AbstractProtein tyrosine phosphatase: phospho-protein complex structure determination, which requires to understand how specificity is achieved at the protein level remains a significant challenge for protein crystallography and cryoEM due to the transient nature of binding interactions. Using rPTPεD1 and phospho-SrcKD as a model system, we established an integrative workflow involving protein crystallography, SAXS and pTyr-tailored MD simulations to reveal the complex formed between rPTPεD1 and phospho-SrcKD, revealing transient protein–protein interactions distal to the active site. To support our finding, we determined the associate rate between rPTPεD1 and phospho-SrcKD and showed that a single mutation on rPTPεD1 disrupts this transient interaction, resulting in the reduction of association rate and activity. Our simulations suggest that rPTPεD1 employs a binding mechanism involving conformational change prior to the engagement of cSrcKD. This integrative approach is applicable to other PTP: phospho-protein complex determination and is a general approach for elucidating transient protein surface interactions.

scholarly journals All-Atom MD Simulations of the HBV Capsid Complexed with AT130 Reveal Secondary and Tertiary Structural Changes and Mechanisms of Allostery

2021 ◽  
Author(s):  
Carolina Pérez Segura ◽  
Boon Chong Goh ◽  
Jodi A. Hadden-Perilla
Keyword(s):  
Small Molecules ◽  
Drug Target ◽  
Structural Changes ◽  
Salt Bridge ◽  
Md Simulations ◽  
Health Concern ◽  
Protein Dimer ◽  
B Virus ◽  
Flexible Protein ◽  
Dynamics Simulations

AbstractThe hepatitis B virus (HBV) capsid is an attractive drug target, relevant to combating viral hepatitis as a major public health concern. Among small molecules known to interfere with capsid assembly, the phenylpropenamides, including AT130, represent an important anti-viral paradigm based on disrupting the timing of genome encapsulation. Crystallographic studies of AT130-bound complexes have been essential in explaining the effects of the small molecule on HBV capsid structure; however, computational examination reveals that key changes attributed to AT130 were erroneous, likely a consequence of interpreting poor resolution arising from a highly flexible protein. Here, all-atom molecular dynamics simulations of an intact AT130-bound HBV capsid reveal that, rather than damaging spike helicity, AT130 enhances the capsid’s ability to recover it. A new conformational state is identified, which can lead to dramatic opening of the intradimer interface and disruption of communication within the spike tip. A novel salt bridge is also discovered, which can mediate contact between the spike tip and fulcrum even in closed conformations, revealing a mechanism of direct communication across these domains. Combined with dynamical network analysis, results describe a connection between the intra- and interdimer interfaces and enable mapping of allostery traversing the entire capsid protein dimer.

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