Mechanical Analysis of Collagen and DNA
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It is known that mechanics plays a central role in many biological events. Tissue can remodel and turnover to adapt to new mechanical environment, such as hypertension and exercising. During the remodeling, hydrolysis of collagen is a key step. It is found that extension will change the cleavage rate of both collagen monomers and fibrils. The specificity of the collagen cleavage site is explained as the unique local mechanical environment of the cleavage site. DNA is another important filament molecule, and its behavior is also regulated by mechanics. The sequence-dependence of mechanical property has been observed, and is related to the specific interaction between proteins and DNA. On the pursuit of understanding the role of mechanics in those biological events as well as connecting atomistic to mesoscale properties of biopolymers, we used molecular dynamics (MD) simulation to study collagen and DNA. In collagen study, from the local bending stiffness calculated around cleavage site, we found it is transitioned from stiff to flexible across the cleavage site, which agrees with the classic model and can be seen as the structural feature recognizable by MMPs. We showed that the α-chain registry can determine the local conformation of collagen, and hence the cleavability of collagen. The resistance of homotrimer form to hydrolysis is interpreted as the stabilization role of arginines downstream to the cleavage site. Homotrimer form is found mainly in fetal tissue and carcinomas, and related to osteogenesis imperfecta. This resistance mechanism can help people to better understand its role in these processes. We further resolved controversial findings in experiments regarding the relationship between extension and collagen cleavage rate published the same year on the same journal. By mimicking the pulling conditions in the experiments, we found it is their different ways of pulling that induces different conformations, and therefore, different relationship of cleavage rate vs extension. This indicates the importance of mechanical environment on collagen. In our DNA investigation, we further developed our triad method to make it being capable for local isotropic mechanics study. We demonstrated the mechanical property is mainly determined at the dinucleotide-level sequence. The sequence-dependent flexibility can be applied to mechanical property prediction of any DNA sequence, as well as DNA nanostructures construction. We found the overwhelmingly used helicoidal parameters are not suitable for dynamic study, due to their degeneracy in describing conformational changes. Based on our data, we built a coarse-grained model that can capture the mechanical properties measured in experiments. This model bridges the atomistic dynamics and mesoscale property of DNA. By using the obtained stiffness and equilibrium data, we calculated energy of crystal structures of dsDNA-protein complexes without non-standard bases and paring. The results provided quantitative insight into the DNA-protein interaction dynamics. We further analyzed DNA methylation, a fundamental epigenetic modification that generates profound impact on gene regulation. We showed methylation generally will cause the immediate neighbor steps to be stiffer, whereas the methylated step itself less affected in mechanics. This is mainly because the steric interaction between methyl groups of methylated cytosine with other groups. We also demonstrated the hydration distribution change upon methylation could play a role in the stiffness variation, as well as affect the binding affinity to different proteins, since hydration force is key in molecular interactions. The findings in this study display influence of methylation in high resolution, and are potentially helpful to elucidate the mechanism of methylation in gene regulation. Currently we are investigating interaction between kinesin-1 motor head and tubulin. Its dimer or tetramer form can walk unidirectionally on microtubules (MTs), in an out-of phase manner. The motion can be attributed to different binding affinity when pulled in different directions and various nucleotide binding modes. We will simulate those different conditions to understand the atomistic mechanism.
Teng, Xiaojing (2016). Mechanical Analysis of Collagen and DNA. Doctoral dissertation, Texas A & M University. Available electronically from