Abstract
Calmodulin (CaM) is a multifunctional calcium-binding protein, which regulates a variety of biochemical processes. CaM acts through its conformational changes and complex formation with its target enzymes. CaM consists of two globular domains (N-lobe and C-lobe) linked by an extended linker region. Upon calcium binding, the N-lobe and C-lobe undergo local conformational changes, followed by a major conformational change of the entire CaM to wrap the target enzyme. However, the regulation mechanisms, such as allosteric interactions, which regulate the large structural changes, are still unclear. In order to investigate the series of structural changes, the free-energy landscape of CaM was obtained by multi-scale divide-and-conquer molecular dynamics (MSDC-MD). The resultant free-energy landscape (FEL) shows that the Ca2+ bound CaM (holo-CaM) would take an experimentally famous elongated structure, which can be formed in the early stage of structural change, by breaking the inter-domain interactions. The FEL also shows that important interactions complete the structural change from the elongated structure to the ring-like structure. In addition, the FEL might give a guiding principle to predict mutational sites in CaM. In this study, it was demonstrated that the movement process of macroscopic variables on the FEL may be diffusive to some extent, and then, the MSDC-MD is suitable to the parallel computation.
Highlights
Calcium ions (Ca2+) act as intracellular messengers that relay information within cells to regulate cellular processes [1,2]
We proposed a method which combines an efficiency of a coarsegrained model (CGM) for conformational search and accuracy of an all-atom model (AAM) named multi-scale divide-and-conquer molecular dynamics (MD) (MSDC-MD) [72] and demonstrated that the free-energy landscape (FEL) of an intrinsically disordered protein, which is one of CaM-binding domain (CaMBD), could be evaluated correctly
The entire FEL (F(v1, v2), T = 300 K, kBT = 0.6 kcal/mol) obtained by multi-scale divide-and-conquer molecular dynamics (MSDC-MD) is shown in Figure 3, which shows that the FEL has a complex multi-valley structure
Summary
Calcium ions (Ca2+) act as intracellular messengers that relay information within cells to regulate cellular processes [1,2]. The information of a transient Ca2+ signal is converted into a wide variety of biochemical changes by Ca2+-binding proteins ( known as Ca2+sensors) through Ca2+-induced conformational changes [3,4]. Calmodulin (CaM) is a ubiquitous Ca2+-sensor found in eukaryotic cells, which activates enzymes, such as kinases and phosphatases, in a Ca2+-dependent manner so that it regulates various biochemical processes. CaM is known to be involved in various cellular processes, such as cell proliferation, apoptosis, muscle contraction, inflammations, immune responses, and long-term potentiation [3,4,10,11,12,13,14,15,16,17,18]. The EF-hand motifs have been found in other Ca2+-
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