Coarse-Grained Modeling and Molecular Dynamics Simulations of Ca2+-Calmodulin.

Jules Nde,Jacob C Ezerski,Pengzhi Zhang,Peter G Wolynes,Wei Lu,Kaitlin Knapp,Margaret S Cheung

doi:10.3389/fmolb.2021.661322

Abstract

Calmodulin (CaM) is a calcium-binding protein that transduces signals to downstream proteins through target binding upon calcium binding in a time-dependent manner. Understanding the target binding process that tunes CaM’s affinity for the calcium ions (Ca2+), or vice versa, may provide insight into how Ca2+-CaM selects its target binding proteins. However, modeling of Ca2+-CaM in molecular simulations is challenging because of the gross structural changes in its central linker regions while the two lobes are relatively rigid due to tight binding of the Ca2+ to the calcium-binding loops where the loop forms a pentagonal bipyramidal coordination geometry with Ca2+. This feature that underlies the reciprocal relation between Ca2+ binding and target binding of CaM, however, has yet to be considered in the structural modeling. Here, we presented a coarse-grained model based on the Associative memory, Water mediated, Structure, and Energy Model (AWSEM) protein force field, to investigate the salient features of CaM. Particularly, we optimized the force field of CaM and that of Ca2+ ions by using its coordination chemistry in the calcium-binding loops to match with experimental observations. We presented a “community model” of CaM that is capable of sampling various conformations of CaM, incorporating various calcium-binding states, and carrying the memory of binding with various targets, which sets the foundation of the reciprocal relation of target binding and Ca2+ binding in future studies.

Highlights

Calmodulin (CaM) is a calcium-binding protein that is present in all eukaryotic cells (Berchtold and Villalobo, 2014; Villalobo et al, 2018; Chin and Means, 2000)
The goal is to create a computational model for CaM accommodating its several key functions including divalent ion binding, conformational dynamics, and target recognition
Each of the 60 memories has a specific conformation of calmodulin which could be helpful in target recognition and target selection; clustering the 60 memories may leave out important conformations that accommodate recognition of a specific target protein

Summary

Introduction

Calmodulin (CaM) is a calcium-binding protein that is present in all eukaryotic cells (Berchtold and Villalobo, 2014; Villalobo et al, 2018; Chin and Means, 2000). Upon sufficient increase in Ca2+ concentration, Ca2+-free CaM transitions to the Ca2+-loaded CaM (Figure 1), exposing the hydrophobic target-binding surfaces of CaM to the solvent (Figure 2) (Barton et al, 2002; Vetter and Leclerc, 2003; Park et al, 2008; Gromiha and Gromiha, 2010; Wu et al, 2012; Fernandes and Oliveira-Brett, 2017) This transition is accompanied by large conformational changes mutually induced by the conformational changes in the CaM-binding target (CaMBT) peptides The important feature that the net charges of Ca2+ ions vary with the conformations of a calciumbinding loop (Zhang et al, 2021), has not been accurately captured in molecular dynamics simulations on calcium-binding proteins

Methods

Results

Conclusion