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Inverse poroelasticity as a fundamental mechanism in biomechanics and mechanobiology.

ABSTRACT: Understanding the mechanisms of deformation of biological materials is important for improved diagnosis and therapy, fundamental investigations in mechanobiology, and applications in tissue engineering. Here we demonstrate the essential role of interstitial fluid mobility in determining the mechanical properties of soft tissues. Opposite to the behavior expected for a poroelastic material, the tissue volume of different collagenous membranes is observed to strongly decrease with tensile loading. Inverse poroelasticity governs monotonic and cyclic responses of soft biomembranes, and induces chemo-mechanical coupling, such that tensile forces are modulated by the chemical potential of the interstitial fluid. Correspondingly, the osmotic pressure varies with mechanical loads, thus providing an effective mechanism for mechanotransduction. Water mobility determines the tissue's ability to adapt to deformation through compaction and dilation of the collagen fiber network. In the near field of defects this mechanism activates the reversible formation of reinforcing collagen structures which effectively avoid propagation of cracks.How soft tissues respond to mechanical load is essential to their biological function. Here, the authors discover that - contrary to predictions of poroelasticity - fluid mobility in collagenous tissues induces drastic volume decrease with tensile loading and pronounced chemo-mechanical coupling.

SUBMITTER: Ehret AE

PROVIDER: S-EPMC5714996 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Butyrylcholinesterase (BChE)-cocaine binding and the fundamental pathway for BChE-catalyzed hydrolysis of cocaine have been studied by molecular modeling, molecular dynamics (MD) simulations, and ab initio calculations. Modeling and simulations indicate that the structures of the prereactive BChE/substrate complexes for (-)-cocaine and (+)-cocaine are all similar to that of the corresponding prereactive BChE/butyrylcholine (BCh) complex. The overall binding of BChE with (-)-cocaine and (+)-cocaine is also similar to that proposed with butyrylthiocholine and succinyldithiocholine, i.e., (-)- or (+)-cocaine first slides down the substrate-binding gorge to bind to Trp-82 and stands vertically in the gorge between Asp-70 and Trp-82 (nonprereactive complex) and then rotates to a position in the catalytic site within a favorable distance for nucleophilic attack and hydrolysis by Ser-198 (prereactive complex). In the prereactive complex, cocaine lies horizontally at the bottom of the gorge. The fundamental catalytic hydrolysis pathway, consisting of acylation and deacylation stages similar to those for ester hydrolysis by other serine hydrolases, was proposed on the basis of the simulated prereactive complex and confirmed theoretically by ab initio reaction coordinate calculations. Both the acylation and deacylation follow a double-proton-transfer mechanism. The calculated energetic results show that within the chemical reaction process the highest energy barrier and Gibbs free energy barrier are all associated with the first step of deacylation. The calculated ratio of the rate constant (k(cat)) for the catalytic hydrolysis to that (k(0)) for the spontaneous hydrolysis is approximately 9.0 x 10(7). The estimated k(cat)/k(0) value of approximately 9.0 x 10(7) is in excellent agreement with the experimentally derived k(cat)/k(0) value of approximately 7.2 x 10(7) for (+)-cocaine, whereas it is approximately 2000 times larger than the experimentally derived k(cat)/k(0) value of approximately 4.4 x 10(4) for (-)-cocaine. All of the results suggest that the rate-determining step of the BChE-catalyzed hydrolysis of (+)-cocaine is the first step of deacylation, whereas for (-)-cocaine the change from the nonprereactive complex to the prereactive complex is rate-determining and has a Gibbs free energy barrier higher than that for the first step of deacylation by approximately 4 kcal/mol. A further analysis of the structural changes from the nonprereactive complex to the prereactive complex reveals specific amino acid residues hindering the structural changes, providing initial clues for the rational design of BChE mutants with improved catalytic activity for (-)-cocaine.

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Inverse poroelasticity as a fundamental mechanism in biomechanics and mechanobiology.

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