Protein-protein docking: Progress in CAPRI rounds 6-12 using a combination of methods: The introduction of steered solvated molecular dynamics

2007 ◽  
Vol 69 (4) ◽  
pp. 816-822 ◽  
Author(s):  
Alexander Heifetz ◽  
Sandeep Pal ◽  
Graham R. Smith
Keyword(s):  
Molecular Dynamics ◽  
Protein Docking ◽  
Combination Of Methods

scholarly journals Protein Docking and Steered Molecular Dynamics Reveal Alternative Regulatory Sites on the SERCA Calcium Transporter

2019 ◽  
Author(s):  
Rebecca F. Alford ◽  
Nikolai Smolin ◽  
Howard S. Young ◽  
Jeffrey J. Gray ◽  
Seth L. Robia
Keyword(s):  
Molecular Dynamics ◽  
Steered Molecular Dynamics ◽  
Protein Docking ◽  
Transport Activity ◽  
Structural Determinants ◽  
Inhibitory Interaction ◽  
Relative Binding ◽  
Inhibitory Site ◽  
Alternative Sites ◽  
Regulatory Sites

AbstractThe transport activity of the calcium ATPase SERCA is modulated by an inhibitory interaction with a 52-residue transmembrane peptide, phospholamban (PLB). Biochemical and structural studies have revealed the primary inhibitory site on SERCA, but PLB has been hypothesized to interact with alternative sites on SERCA that are distinct from the inhibitory site. The present study was undertaken to test these hypotheses and explore structural determinants of SERCA regulation by PLB. Steered molecular dynamics (SMD) and membrane protein-protein docking experiments were performed to investigate the apparent affinity of PLB interactions with candidate sites on SERCA. We modeled the relative binding of PLB to several different conformations of SERCA, representing different enzymatic states sampled during the calcium transport catalytic cycle. Overall, the SMD and docking experiments suggest that the canonical binding site is preferred, but also provide evidence for alternative sites that are favorable for certain conformational states of SERCA.

Rational design of the survivin/CDK4 complex by combining protein–protein docking and molecular dynamics simulations

2012 ◽  
Vol 19 (4) ◽  
pp. 1507-1514 ◽  
Author(s):  
Jana Selent ◽  
Agnieszka A. Kaczor ◽  
Ramon Guixà-González ◽  
Pau Carrió ◽  
Manuel Pastor ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Molecular Dynamics Simulations ◽  
Rational Design ◽  
Protein Docking ◽  
Dynamics Simulations

scholarly journals Ranking protein-protein docking results using steered molecular dynamics and potential of mean force calculations

2016 ◽  
Vol 37 (20) ◽  
pp. 1861-1865 ◽  
Author(s):  
Laura J. Kingsley ◽  
Juan Esquivel-Rodríguez ◽  
Ying Yang ◽  
Daisuke Kihara ◽  
Markus A. Lill
Keyword(s):  
Molecular Dynamics ◽  
Steered Molecular Dynamics ◽  
Protein Docking ◽  
Potential Of Mean Force

scholarly journals SARS-CoV-2 spike protein unlikely to bind to integrins via the Arg-Gly-Asp (RGD) motif of the Receptor Binding Domain: evidence from structural analysis and microscale accelerated molecular dynamics

2021 ◽  
Author(s):  
Houcemeddine Othman ◽  
Haifa Ben Messaoud ◽  
Oussema Khamessi ◽  
Hazem Ben Mabrouk ◽  
Kais Ghedira ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Structural Analysis ◽  
Receptor Binding ◽  
Normal Mode Analysis ◽  
Protein Docking ◽  
Binding Domain ◽  
Mode Analysis ◽  
Receptor Binding Domain ◽  
Rgd Motif ◽  
Accelerated Molecular Dynamics

The Receptor Binding Domain (RBD) of SARS-CoV-2 virus harbors a sequence of Arg-Gly-Asp tripeptide named RGD motif, which has also been identified in extracellular matrix proteins that bind integrins as well as other disintegrins and viruses. Accordingly, integrins have been proposed as host receptors for SARS-CoV-2. The hypothesis was supported by sequence and structural analysis. However, given that the microenvironment of the RGD motif imposes structural hindrance to the protein-protein association, the validity of this hypothesis is still uncertain. Here, we used normal mode analysis, accelerated molecular dynamics microscale simulation, and protein-protein docking to investigate the putative role of RGD motif of SARS-CoV-2 RBD for interacting with integrins. We found, by molecular dynamics, that neither RGD motif nore its microenvironment show any significant conformational shift in the RBD structure. Highly populated clusters were used to run a protein-protein docking against three RGD-binding integrin types, showing no capability of the RBD domain to interact with the RGD binding site. Moreover, the free energy landscape revealed that the RGD conformation within RBD could not acquire an optimal geometry to allow the interaction with integrins. Our results highlighted different structural features of the RGD motif that may prevent its involvement in the interaction with integrins. We, therefore, suggest, in the case where integrins are confirmed to be the direct host receptors for SARS-CoV-2, a possible involvement of other residues to stabilize the interaction.

scholarly journals Interaction of a sarcolipin pentamer and monomer with the sarcoplasmic reticulum calcium pump, SERCA

2019 ◽  
Author(s):  
J. P. Glaves ◽  
J. O. Primeau ◽  
P. A. Gorski ◽  
L. M. Espinoza-Fonseca ◽  
M. J. Lemieux ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Sarcoplasmic Reticulum ◽  
Molecular Dynamics Simulations ◽  
Maximal Activity ◽  
Protein Docking ◽  
The Novel ◽  
Wild Type ◽  
Transmembrane Segment ◽  
Dynamics Simulations ◽  
Sarcoplasmic Reticulum Calcium

ABSTRACTThe sequential rise and fall of cytosolic calcium underlies the contraction-relaxation cycle of muscle cells. While contraction is initiated by the release of calcium from the sarcoplasmic reticulum, muscle relaxation involves the active transport of calcium back into the sarcoplasmic reticulum. This re-uptake of calcium is catalysed by the sarco-endoplasmic reticulum Ca2+-ATPase (SERCA), which plays a lead role in muscle contractility. The activity of SERCA is regulated by small membrane protein subunits, most well-known being phospholamban (PLN) and sarcolipin (SLN). SLN physically interacts with SERCA and differentially regulates contractility in skeletal and atrial muscle. SLN has also been implicated in skeletal muscle thermogenesis. Despite these important roles, the structural mechanisms by which SLN modulates SERCA-dependent contractility and thermogenesis remain unclear. Here, we functionally characterized wild-type SLN and a pair of mutants, Asn4-Ala and Thr5-Ala, which yielded gain-of-function behavior comparable to what has been found for PLN. Next, we analyzed twodimensional crystals of SERCA in the presence of wild-type SLN by electron cryo-microscopy. The fundamental units of the crystals are anti-parallel dimer ribbons of SERCA, known for decades as an assembly of calcium-free SERCA molecules induced by the addition of decavanadate. A projection map of the SERCA-SLN complex was determined to a resolution of 8.5 Å, which allowed the direct visualization of a SLN pentamer. The SLN pentamer was found to interact with transmembrane segment M3 of SERCA, though the interaction appeared to be indirect and mediated by an additional density consistent with a SLN monomer. This SERCA-SLN complex correlated with the ability of SLN to decrease the maximal activity of SERCA, which is distinct from the ability of PLN to increase the maximal activity of SLN. Protein-protein docking and molecular dynamics simulations provided models for the SLN pentamer and the novel interaction between SERCA and a SLN monomer.STATEMENT OF SIGNIFICANCEThis research article describes a novel complex of the sarcoplasmic reticulum calcium pump SERCA and its regulatory subunit sarcolipin. Given the potential role of sarcolipin in skeletal muscle non-shivering thermogenesis, the interactions between SERCA and sarcolipin are of critical importance. Using complementary approaches of functional analysis, electron crystallography, and molecular dynamics simulations, we demonstrate an inherent interaction between SERCA, a sarcolipin monomer, and a sarcolipin pentamer. The interaction involves transmembrane segment M3 of SERCA, which allows sarcolipin to decrease the maximal activity or turnover rate of SERCA. Protein-protein docking and molecular dynamics simulations provided models for the SLN pentamer and the novel interaction between SERCA and a SLN monomer.

Computational Approaches for Elucidating Protein-Protein Interactions in Cation Channel Signaling

2020 ◽  
Vol 21 (2) ◽  
pp. 179-192
Author(s):  
Baichun Hu ◽  
Xiaoming Zheng ◽  
Ying Wang ◽  
Jian Wang ◽  
Fengjiao Zhang
Keyword(s):  
Molecular Dynamics ◽  
Molecular Dynamics Simulation ◽  
Homology Modeling ◽  
Protein Interactions ◽  
Protein Docking ◽  
Cation Channel ◽  
Dynamics Simulation ◽  
Protein Protein Interactions ◽  
Molecular Graphics ◽  
Computational Approaches

Background: The lipid bilayer of the plasma membrane is impermeable to ions, yet changes in the flux of ions across the cell membrane are critical regulatory events in cells. Because of their regulatory roles in a range of physiological processes, such as electrical signaling in muscles and neurons, to name a few, these proteins are one of the most important drug targets. Objective: This review mainly focused on the computational approaches for elucidating proteinprotein interactions in cation channel signaling. Discussion: Due to continuously advanced facilities and technologies in computer sciences, the physical contacts of macromolecules of channel structures have been virtually visualized. Indeed, techniques like protein-protein docking, homology modeling, and molecular dynamics simulation are valuable tools for predicting the protein complex and refining channels with unreleased structures. Undoubtedly, these approaches will greatly expand the cation channel signaling research, thereby speeding up structure-based drug design and discovery. Conclusion: We introduced a series of valuable computational tools for elucidating protein-protein interactions in cation channel signaling, including molecular graphics, protein-protein docking, homology modeling, and molecular dynamics simulation.

scholarly journals Combining enhanced sampling with experiment-directed simulation of the GYG peptide

2018 ◽  
Vol 17 (03) ◽  
pp. 1840007 ◽  
Author(s):  
Dilnoza B. Amirkulova ◽  
Andrew D. White
Keyword(s):  
Molecular Dynamics ◽  
Molecular Dynamics Simulations ◽  
Chemical Shifts ◽  
Parallel Tempering ◽  
Collective Variables ◽  
Novel Approach ◽  
Sampling Problem ◽  
Combination Of Methods ◽  
Dynamics Simulations ◽  
Explicit Water

Experiment-directed simulation (EDS) is a technique to minimally bias molecular dynamics simulations to match experimentally observed results. The method improves accuracy but does not address the sampling problem of molecular dynamics simulations of large systems. This work combines EDS with both the parallel-tempering or parallel-tempering well-tempered ensemble replica-exchange methods to enhance sampling. These methods are demonstrated on the GYG tripeptide in explicit water. The collective variables biased by EDS are chemical shifts, where the set-points are determined by NMR experiments. The results show that it is possible to enhance sampling with either parallel-tempering and parallel-tempering well-tempered ensemble in the EDS method. This combination of methods provides a novel approach for both accurately and exhaustively simulating biological systems.

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