Coarse‐Grained Simulations of Transitions in the E2‐to‐E1 Conformations for Ca ATPase (SERCA) Show Entropy–Enthalpy Compensation

• Published in: Journal of molecular biology Vol. 422; no. 4; pp. 575 - 593
• Main Authors: Nagarajan, Anu, Andersen, Jens Peter, Woolf, Thomas B.
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 28.09.2012
• Subjects: A-M3 linker region; adenosinetriphosphatase; Animals; Ca super(2+)-transporting ATPase; Calcium - metabolism; Computer applications; conformational change; Enthalpy; Entropy; Ionizing radiation; Kinetics; Membrane proteins; Membrane Proteins - chemistry; Membrane Proteins - metabolism; membrane transport; Membrane Transport Proteins - chemistry; Membrane Transport Proteins - metabolism; Models, Molecular; Molecular dynamics; Molecular Dynamics Simulation; mutants; Mutation; mutations impacting kinetics; Protein Interaction Domains and Motifs; Protein Structure, Tertiary; Protein transport; Rabbits; Sampling; Sarcoplasmic Reticulum Calcium-Transporting ATPases - chemistry; Sarcoplasmic Reticulum Calcium-Transporting ATPases - metabolism; Thermodynamics; transport proteins; X-radiation; membrane transport; A-M3 linker region; DIMS; molecular dynamics; conformational change; WT; mutations impacting kinetics
• ISSN: 0022-2836; 1089-8638
• DOI: 10.1016/j.jmb.2012.06.001

SERCA is a membrane transport protein that has been extensively studied. There are a large number of highly resolved X-ray structures and several hundred mutations that have been characterized functionally. Despite this, the molecular details of the catalytic cycle, a cycle that includes large conformational changes, is not fully understood. In this computational study, we provide molecular dynamics descriptions of conformational changes during the E2→E1 transitions. The motivating point for these calculations was a series of insertion mutants in the A-M3 linker region that led to significant shifts in measured rates between the E2 and E1 states, as shown by experimental characterization. Using coarse-grained dynamic importance sampling within the context of a population shift framework, we sample on the intermediates along the transition pathway to address the mechanism for the conformational changes and the effects of the insertion mutations on the kinetics of the transition. The calculations define an approximation for the relative changes in entropy and enthalpy along the transition. These are found to be important for understanding the experimentally observed differences in rates. In particular, the interactions between cytoplasmic domains, water interactions, and the shifts in protein degrees of freedom with the insertion mutations show mutual compensation for the E2→E1 transitions in wild‐type and mutant systems. [Display omitted]