Protein-restricted maternal diet during lactation decreases type I and type III tropocollagen synthesis in the skin of mice offspring.

We investigated the effects of a low protein (LP) maternal diet during lactation on type I and III tropocollagen synthesis in infant mouse skin. The LP diet decreased the levels of type I and III tropocollagen proteins and COL1A1 and COL3A1 mRNA. Thus, the protein composition of the maternal perinatal diet may influence the skin health of offspring.

Effect of changes in tropocollagen residue sequence and hydroxyapatite mineral texture on the strength of ideal nanoscale tropocollagen-hydroxyapatite biomaterials.

Changes in mineral texture (e.g. hydroxyapatite (HAP) or aragonite) and polypeptide (e.g. tropocollagen (TC)) residue sequence are characteristic features of a disease known as osteogenesis imperfecta (OI). In OI, different possibilities of changes in polypeptide residue sequence as well as changes in polypeptide helix replacement (e.g. 3 alpha1 chains instead of 2 alpha1 and 1 alpha2 chain in OI murine) exist. The cross section of the HAP crystals could be needle like or plate like. Such texture and residue sequence related changes can significantly affect the material strength at the nanoscale. In this work, a mechanistic understanding of such factors in determining strength of nanoscale TC-HAP biomaterials is presented using three dimensional molecular dynamics (MD) simulations. Analyses point out that the peak interfacial strength for failure is the highest for supercells with plate shaped HAP crystals. TC molecules with higher number of side chain functional groups impart higher strength to the TC-HAP biomaterials at the nanoscale. Overall, HAP crystal shape variation, the direction of applied loading with respect to the relative TC-HAP orientation, and the number of side chain functional groups in TC molecules are the factor that affect TC-HAP biomaterial strength in a significant manner.

Alport syndrome mutations in type IV tropocollagen alter molecular structure and nanomechanical properties.

Alport Syndrome is a genetic disease characterized by breakdown of the glomerular basement membrane (GBM) around blood vessels in the kidney, leading to kidney failure in most patients. It is the second most inherited kidney disease in the US, and many other symptoms are associated with the disease, including hearing loss and ocular lesions. Here we probe the molecular level structure-property relationships of this disease using a bottom-up computational materiomics approach implemented through large-scale molecular dynamics simulation. Since the GBM is under constant mechanical loading due to blood flow, changes in mechanical properties due to amino acid mutations may be critical in the symptomatic GBM breakdown seen in Alport Syndrome patients. Through full-atomistic simulations in explicit solvent, the effects of single-residue glycine substitution mutations of varying clinical severity are studied in short segments of type IV tropocollagen molecules. The segments with physiological amino acid sequences are equilibrated and then subjected to tensile loading. Major changes are observed at the single molecule level of the mutated sequence, including a bent shape of the structures after equilibration (with the kink located at the mutation site) and a significant alteration of the molecules' stress-strain responses and stiffnesses. These results suggest that localized structural changes at amino acid level induce severe alterations of the molecular properties. Our study opens a new approach in pursuing a bottom-up multi-scale analysis of this disease.

Molecular and mesoscale mechanisms of osteogenesis imperfecta disease in collagen fibrils.

Osteogenesis imperfecta (OI) is a genetic disorder in collagen characterized by mechanically weakened tendon, fragile bones, skeletal deformities, and in severe cases, prenatal death. Although many studies have attempted to associate specific mutation types with phenotypic severity, the molecular and mesoscale mechanisms by which a single point mutation influences the mechanical behavior of tissues at multiple length scales remain unknown. We show by a hierarchy of full atomistic and mesoscale simulation that OI mutations severely compromise the mechanical properties of collagenous tissues at multiple scales, from single molecules to collagen fibrils. Mutations that lead to the most severe OI phenotype correlate with the strongest effects, leading to weakened intermolecular adhesion, increased intermolecular spacing, reduced stiffness, as well as a reduced failure strength of collagen fibrils. We find that these molecular-level changes lead to an alteration of the stress distribution in mutated collagen fibrils, causing the formation of stress concentrations that induce material failure via intermolecular slip. We believe that our findings provide insight into the microscopic mechanisms of this disease and lead to explanations of characteristic OI tissue features such as reduced mechanical strength and a lower cross-link density. Our study explains how single point mutations can control the breakdown of tissue at much larger length scales, a question of great relevance for a broad class of genetic diseases.

Single molecule effects of osteogenesis imperfecta mutations in tropocollagen protein domains.

Osteogenesis imperfecta (OI) is a genetic disease characterized by fragile bones, skeletal deformities and, in severe cases, prenatal death that affects more than 1 in 10,000 individuals. Here we show by full atomistic simulation in explicit solvent that OI mutations have a significant influence on the mechanical properties of single tropocollagen molecules, and that the severity of different forms of OI is directly correlated with the reduction of the mechanical stiffness of individual tropocollagen molecules. The reduction of molecular stiffness provides insight into the molecular-scale mechanisms of the disease. The analysis of the molecular mechanisms reveals that physical parameters of side-chain volume and hydropathy index of the mutated residue control the loss of mechanical stiffness of individual tropocollagen molecules. We propose a model that enables us to predict the loss of stiffness based on these physical characteristics of mutations. This finding provides an atomistic-level mechanistic understanding of the role of OI mutations in defining the properties of the basic protein constituents, which could eventually lead to new strategies for diagnosis and treatment the disease. The focus on material properties and their role in genetic diseases is an important, yet so far only little explored, aspect in studying the mechanisms that lead to pathological conditions. The consideration of how material properties change in diseases could lead to a new paradigm that may expand beyond the focus on biochemical readings alone and include a characterization of material properties in diagnosis and treatment, an effort referred to as materiomics.