One efficient method is replica-exchange molecular dynamics simulation (Sugita and Okamoto 1999)

One efficient method is replica-exchange molecular dynamics simulation (Sugita and Okamoto 1999). antibodies through controlling allosteric networks in IgG molecules. Keywords: Immunoglobulin G, Antibody, Fc PSEN2 receptor, N-glycan, Molecular dynamics simulation, Answer scattering, X-ray crystallography, Nuclear magnetic resonance spectroscopy, Core fucosylation, Dynamic conformational ensemble Introduction Immunoglobulin G (IgG) is usually a glycoprotein composed of multiple homologous domains (the so-called Ig domains) and plays key functions as an immune system antibody (Chiu et al. 2019) (Fig.?1). This glycoprotein consists of two identical light chains, each divided into VL and CL domains, PF-04217903 and two identical heavy chains, each made up of VH, CH1, CH2, and CH3 domains. CH1 and CH2 domains are connected by a protease-susceptible hinge segment. Cleavage of this segment gives rise to two Fab fragments constituted by VL, VH, CL, and CH1 domains and one Fc fragment constituted by two CH2 and two CH3. Open in a separate windows Fig.?1 Schematic drawing of IgG. An IgG molecule is usually characterized by a multiple domain name modular structure with conserved N-glycosylation in Fc and significant freedom for internal motion Major functions of IgG are acknowledgement of antigens on surfaces of invading viruses and bacteria and recruitment of effector molecules, such as match component C1 and Fc receptors (FcRs), for removal PF-04217903 of such pathogens. Thus, IgG serves as a hub that links these two functions. VH and VL domains are structurally variable and are responsible for antigen acknowledgement. The remaining domains are much less divergent but are classified into several isotypes. The constant region of the IgG heavy chain defines subclassesIgG1C4 in humans. VH and VL domains each display PF-04217903 three hypervariable loops that are directly involved in specific antigen binding and are thus often referred to as complementarity-determining regions (CDRs). Each CH2 domain name of Fc homodimer possesses one conserved N-glycosylation site (Asn297) A biantennary complex-type oligosaccharide is usually expressed at this site, with microheterogeneity resulting from nonreducing terminal fucose (Fuc), galactose (Gal), bisecting N-acetylglucosamine (GlcNAc), and sialic acid residues (Yamaguchi et al. 2007). This N-glycosylation is essential for interactions with effector molecules, which are particularly affected by terminal structures of N-glycans. Currently, IgGs are widely used for detection, quantification, and characterization of biological and pathological molecules and as biopharmaceuticals that target diseases, including cancers. A variety of designed IgG antibodies and their derivatives have been developed and utilized for diagnostic and therapeutic purposes (Chiu et al. 2019). The structure of IgG is usually characterized by considerable conformational flexibility and plasticity, which are supposed to be of relevance to antigen binding and interactions with the effectors (Jay et al. 2018; Yang et al. 2017). An IgG molecule possesses hierarchical degrees of freedom in internal motion across numerous spatiotemporal scales. This conformational dynamic of IgG is critical PF-04217903 for design and engineering of recombinant antibodies with enhanced functionality for interactions with antigens and effector molecules. In this review, dynamic views of IgG structures are outlined, highlighting the importance of integration of experimental and computational methods. Experimental methods for investigating IgG conformational dynamics Early X-ray crystallographic studies of monoclonal IgGs and their light chains derived from multiple myeloma patients revealed their modular structuresIg domains exhibiting longitudinal and transverse interactions within Fab portions (Schiffer et al. 1973; Edmundson et al. 1975). However, crystal structures provided no interpretable electron density for the Fc portion (Colman et al. 1976; Marquart et al. 1980). In contrast, crystallographic data of naturally occurring IgG mutants that lack hinge segments were able to visualize both Fab and Fc (Silverton et al. 1977; Rajan et al. 1983). These findings suggested that internal motion of IgG molecules is attributable.