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.

scholarly journals Protein docking and steered molecular dynamics suggest alternative phospholamban-binding sites on the SERCA calcium transporter

2020 ◽  
Vol 295 (32) ◽  
pp. 11262-11274
Author(s):  
Rebecca F. Alford ◽  
Nikolai Smolin ◽  
Howard S. Young ◽  
Jeffrey J. Gray ◽  
Seth L. Robia
Keyword(s):  
Molecular Dynamics ◽  
Binding Sites ◽  
Structural Model ◽  
Steered Molecular Dynamics ◽  
Protein Docking ◽  
Structural Determinants ◽  
Inhibitory Interaction ◽  
Physical Measurements ◽  
Inhibitory Site ◽  
Regulatory Complex

The transport activity of the sarco(endo)plasmic reticulum calcium ATPase (SERCA) in cardiac myocytes is modulated by an inhibitory interaction with a transmembrane peptide, phospholamban (PLB). Previous biochemical studies have revealed that PLB interacts with a specific inhibitory site on SERCA, and low-resolution structural evidence suggests that PLB interacts with distinct alternative sites on SERCA. High-resolution details of the structural determinants of SERCA regulation have been elusive because of the dynamic nature of the regulatory complex. In this study, we used computational approaches to develop a structural model of SERCA–PLB interactions to gain a mechanistic understanding of PLB-mediated SERCA transport regulation. We combined steered molecular dynamics and membrane protein–protein docking experiments to achieve both a global search and all-atom force calculations to determine the relative affinities of PLB for candidate sites on SERCA. We modeled the binding of PLB to several SERCA conformations, representing different enzymatic states sampled during the calcium transport catalytic cycle. The results of the steered molecular dynamics and docking experiments indicated that the canonical PLB-binding site (comprising transmembrane helices M2, M4, and M9) is the preferred site. This preference was even more stringent for a superinhibitory PLB variant. Interestingly, PLB-binding specificity became more ambivalent for other SERCA conformers. These results provide evidence for polymorphic PLB interactions with novel sites on M3 and with the outside of the SERCA helix M9. Our findings are compatible with previous physical measurements that suggest that PLB interacts with multiple binding sites, conferring dynamic responsiveness to changing physiological conditions.

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

Massively Parallel Implementation of Steered Molecular Dynamics in Tinker-HP: Comparisons of Polarizable and Non-Polarizable Simulations of Realistic Systems

2019 ◽  
Author(s):  
Frédéric Célerse ◽  
Louis Lagardere ◽  
Étienne Derat ◽  
Jean-Philip Piquemal
Keyword(s):  
Molecular Dynamics ◽  
Parallel Implementation ◽  
Steered Molecular Dynamics ◽  
Massively Parallel

This paper is dedicated to the massively parallel implementation of Steered Molecular Dynamics in the Tinker-HP softwtare. It allows for direct comparisons of polarizable and non-polarizable simulations of realistic systems.

Massively Parallel Implementation of Steered Molecular Dynamics in Tinker-HP: Comparisons of Polarizable and Non-Polarizable Simulations of Realistic Systems

2019 ◽  
Author(s):  
Frédéric Célerse ◽  
Louis Lagardere ◽  
Étienne Derat ◽  
Jean-Philip Piquemal
Keyword(s):  
Molecular Dynamics ◽  
Parallel Implementation ◽  
Steered Molecular Dynamics ◽  
Massively Parallel

This paper is dedicated to the massively parallel implementation of Steered Molecular Dynamics in the Tinker-HP softwtare. It allows for direct comparisons of polarizable and non-polarizable simulations of realistic systems.

scholarly journals Qualitative Prediction of Ligand Dissociation Kinetics from Focal Adhesion Kinase Using Steered Molecular Dynamics

Life ◽  
2021 ◽  
Vol 11 (2) ◽  
pp. 74
Author(s):  
Justin Spiriti ◽  
Chung F. Wong
Keyword(s):  
Molecular Dynamics ◽  
Drug Discovery ◽  
Focal Adhesion Kinase ◽  
Focal Adhesion ◽  
Early Stage ◽  
Steered Molecular Dynamics ◽  
Drug Binding ◽  
Binding Kinetics ◽  
Dissociation Kinetics ◽  
Binding Characteristics

Most early-stage drug discovery projects focus on equilibrium binding affinity to the target alongside selectivity and other pharmaceutical properties. Since many approved drugs have nonequilibrium binding characteristics, there has been increasing interest in optimizing binding kinetics early in the drug discovery process. As focal adhesion kinase (FAK) is an important drug target, we examine whether steered molecular dynamics (SMD) can be useful for identifying drug candidates with the desired drug-binding kinetics. In simulating the dissociation of 14 ligands from FAK, we find an empirical power–law relationship between the simulated time needed for ligand unbinding and the experimental rate constant for dissociation, with a strong correlation depending on the SMD force used. To improve predictions, we further develop regression models connecting experimental dissociation rate with various structural and energetic quantities derived from the simulations. These models can be used to predict dissociation rates from FAK for related compounds.

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