Abstract:Leeuw (2017) Computational study of glucosepane-water and hydrogen bond formation: an electron topology and orbital analysis, Journal of Biomolecular Structure and Dynamics, 35:5, 1127-1137, DOI: 10.1080/07391102.2016 The collagen protein provides tensile strength to the extracellular matrix in addition to localising cells, proteins and protein cofactors. Collagen is susceptible to a build up of glycation modifications as a result of an exceptionally long half-life. Glucosepane is a collagen cross-linking ad… Show more
“…1 and Supplementary note 1). Previous work has demonstrated that glucosepane is very hydrophilic [ 27 ] and may therefore be responsible for the higher water content detected in the tendon tissue from old donors. Fig.…”
Collagen glycation, and in particular the formation of advanced glycation end-product (AGE) crosslinks, plays a central role in the ageing process and in many of the long-term complications of diabetes. Glucosepane, the most abundant and relevant AGE crosslink, has been suggested to increase the stiffness of tissue and reduce its solubility, although no evidence is available concerning the mechanisms. We have used a combination of computational and experimental techniques to study a collagen-rich tissue with a relatively simple organisation to further our understanding of the impact of glucosepane on the structural and physical properties of collagen fibrils. Our work shows that glucosepane levels increase dramatically in aged tendon tissue and are associated with the reduced density of collagen packing and increased porosity to water molecules. Our studies provide the basis to understand many of the tissue dysfunctions associated with ageing and diabetes across a range of different tissues types.
“…1 and Supplementary note 1). Previous work has demonstrated that glucosepane is very hydrophilic [ 27 ] and may therefore be responsible for the higher water content detected in the tendon tissue from old donors. Fig.…”
Collagen glycation, and in particular the formation of advanced glycation end-product (AGE) crosslinks, plays a central role in the ageing process and in many of the long-term complications of diabetes. Glucosepane, the most abundant and relevant AGE crosslink, has been suggested to increase the stiffness of tissue and reduce its solubility, although no evidence is available concerning the mechanisms. We have used a combination of computational and experimental techniques to study a collagen-rich tissue with a relatively simple organisation to further our understanding of the impact of glucosepane on the structural and physical properties of collagen fibrils. Our work shows that glucosepane levels increase dramatically in aged tendon tissue and are associated with the reduced density of collagen packing and increased porosity to water molecules. Our studies provide the basis to understand many of the tissue dysfunctions associated with ageing and diabetes across a range of different tissues types.
“…Water molecules are implicated in many important biological processes (de Beer, Vermeulen, & Oostenbrink, 2010;Likic, Juranic, Macura, & Prendergast, 2000;Nash, Saßmannshausen, Bozec, Birch, & de Leeuw, 2017;Uroshlev et al, 2016). The crystal structures of FABP5 (pdb id 1B56) and CRABP-II (pdb id 2CBS) had water molecules present: 39 water molecules in the FABP5 crystal structure, 6 of which are within 4 Å of the bound ligand, and 53 water molecules in the CRABP-II crystal structure, only 2 of which are within 4 Å of the bound ligand.…”
Structural and dynamic properties from a series of 300 ns molecular dynamics, MD, simulations of two intracellular lipid binding proteins, iLBPs, (Fatty Acid Binding Protein 5, FABP5, and Cellular Retinoic Acid Binding Protein II, CRABP-II) in both the apo form and when bound with retinoic acid reveal a high degree of protein and ligand flexibility. The ratio of FABP5 to CRABP-II in a cell may determine whether it undergoes natural apoptosis or unrestricted cell growth in the presence of retinoic acid. As a result, FABP5 is a promising target for cancer therapy. The MD simulations presented here reveal distinct differences in the two proteins and provide insight into the binding mechanism. CRABP-II is a much larger, more flexible protein that closes upon ligand binding, where FABP5 transitions to an open state in the holo form. The traditional understanding obtained from crystal structures of the gap between two β-sheets of the β-barrel common to iLBPs and the α-helix cap that forms the portal to the binding pocket is insufficient for describing protein conformation (open vs. closed) or ligand entry and exit. When the high degree of mobility between multiple conformations of both the ligand and protein are examined via MD simulation, a new mode of ligand motion that improves understanding of binding dynamics is revealed.
“…31 The ωB97X-D functional has been employed to study systems where hydrogen bonds play a relevant role. 32,33 We characterized the nature of the stationary points according to their second order Hessian matrix: minimum energy points on the potential energy surface showed only positive eigenvalues and transition states showed one and only one negative eigenvalue. Implicit solvation was considered in all steps with the self-consistent reaction field (SCRF) option of Gaussian09, using the integral equation formalism variant of the polarizable continuum model (IEFPCM) 34,35 with water (ε = 78.35) as solvent.…”
Density functional theory calculations (ωB97X-D/6-311++G(d,p)) are employed to investigate an alternative pathway for Prins-like cyclization. Although strong acids usually catalyze this reaction, 4-amino-1,3-dioxanes are rapidly obtained in high yields without catalyst when benzenamines and acetaldehyde react at low temperatures, in aqueous medium. Considering these conditions, we applied a supermolecule model with explicit water molecules to compute the mechanism for 4-amino-1,3-dioxanes formation from the reactants. The structure of the primary solvation shell was determined by Metropolis Monte Carlo method. In the Prins-cyclization step, we found an unpredicted pathway with non-ionic transition structures or intermediates. Explicit water molecules establish a net of hydrogen bonds allowing prototropism, maintaining the electrical neutrality in the system while two protons transfer occurs. To provide data to further experimental confirmation of this hypothesis, we estimated the kinetic isotope effect for the reaction. We also investigated the use of aliphatic amines, which indicates that the reaction may be of a broader application than first observed experimentally.
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