The sarcoplasmic reticulum Ca²⁺ ATPase (SERCA) is a membrane-bound pump that 
utilizes ATP to drive calcium ions from the myocyte cytosol against the higher 
calcium concentration in the sarcoplasmic reticulum. Conformational transitions 
associated with Ca²⁺-binding are important to its catalytic function. We have 
identified collective motions that partition SERCA crystallographic structures 
into multiple catalytically-distinct states using principal component analysis. 
Using Brownian dynamics simulations, we demonstrate the important contribution 
of surface-exposed, polar residues in the diffusional encounter of Ca²⁺. 
Molecular dynamics simulations indicate the role of Glu309 gating in binding 
Ca²⁺, as well as subsequent changes in the dynamics of SERCA's cytosolic 
domains. Together these data provide structural and dynamical insights into a 
multistep process involving Ca²⁺ binding and catalytic transitions.