Predicting reaction behavior of tethered polymers in shear flow.

Kinetics of force-mediated chemical reactions of end-tethered polymers with varying chain length N in varying shear rate flow γ̇ are explored via coarse-grained Brownian dynamics simulations. At fixed γ̇, force F along a polymer increases linearly with N as previously predicted; however, contrary to existing theory, the F(N) slope increases for N above a transition length that exhibits minimal dependence on γ̇. Force profiles are used in a stochastic model of a force-mediated reaction to compute the time for x percent of a polymer population to experience a reaction, tx. Observations are insensitive to the selected value of x in that tx data for varying N and γ̇ can be consistently collapsed onto a single curve via appropriate scaling, with one master curve for systems below the transition N (small N) and another for those above (large N). Different force scaling for small and large N results in orders of magnitude difference in force-mediated reaction kinetics as represented by the population response time. Data presented illustrate the possibility of designing mechano-reactive polymer populations with highly controlled response to flow across a range in γ̇.

Replica-averaging: An algorithm to study mechano-reactive processes for polymers under flow conditions.

A new method based on quasi-independent parallel simulation approach, replica-averaging, has been developed to study the influence of flow on mechanical force-mediated polymer processes, such as denaturation and breaking of bonds. This method considerably mitigates the unphysical prediction of force-mediated events inherent in Brownian dynamics (BD) polymer chain simulations that employ instantaneous force profile-based criteria to identify the occurrence of such events. This inaccuracy in predicting force-mediated event kinetics is due to high fluctuations of the instantaneous force profile around the average force. Replica-averaging reduces such high fluctuation effects by computing a force profile that faithfully represents the average force profile of the polymer chain conformation, which is then used to predict reactive events. For transient conformation conditions, the replica-averaged method more accurately predicts the mechano-reactive kinetics than the time-averaged method typically employed to reduce the unphysical prediction of force-mediated events in BD simulations. Furthermore, the influence of the proposed replica-averaging method parameters on the accuracy of predicting the true average force profile along the polymer is discussed.

Flow-regulated nucleation protrusion theory for collapsed polymers.

The globular-stretch transition of a collapsed polymer in low strain rate elongational flow is studied using polymeric protrusion kinetics scaling laws and numerical simulation. Results demonstrate the influence of fluid flow on the occurrence probability of long-length thermally nucleated polymeric protrusions, which regulate collapsed polymer unfolding in low strain rate flows. Further, we estimate that the globular-stretch transition rate (k_{s}) in low strain rate (∈[over ̇]) elongational flows varies as k_{s}∼e^{-α∈[over ̇]^{-1}}. Results here reveal that the existing approach of neglecting the effects of fluid flow on thermally nucleated protrusions distribution is not valid for analyzing polymer unfolding behavior in low strain rate flows. Neglecting such an effect overestimates the constant α in the scaling law of transition rate (k_{s}∼e^{-α∈[over ̇]^{-1}}) by a factor of 2.

Predicting pathological von Willebrand factor unraveling in elongational flow.

The globular-to-unraveled conformation transition of von Willebrand factor (vWF), a large polymeric glycoprotein in human blood plasma, is a crucial step in the process of clotting at sites of vascular injury. However, unraveling of vWF multimers in uninjured vasculature can lead to pathology (i.e., thrombus formation or degradation of vWF proteins by enzyme ADAMTS13, making them nonfunctional). To identify blood flow conditions that might induce pathological unraveling of vWF multimers, here we have computed the globular-to-unraveled transition rate of vWF multimers subjected to varying strain rate elongational flow by employing an enhanced sampling technique, the weighted ensemble method. Weighted ensemble sampling was employed instead of standard brute-force simulations because pathological blood flow conditions can induce undesired vWF unraveling on timescales potentially inaccessible to standard simulation methods. Results here indicate that brief but periodic exposure of vWF to the elongational flow of strain rate greater than or equal to 2500 s-1 represents a source of possible pathology caused by the undesired unraveling of vWF multimers.

A mechano-reactive coarse-grained model of the blood-clotting agent von Willebrand factor.

The von Willebrand Factor (vWF) is a large blood glycoprotein that aids in hemostasis. Within each vWF monomer, the A2 domain hosts a cleavage site for enzyme ADAMTS13, which regulates the size of vWF multimers. This cleavage site can only be exposed when an A2 domain unfolds, and the unfolding reaction energy landscape is highly sensitive to the force conditions on the domain. Based on previous optical tweezer experimental results, we advance here a new activated A2 monomer model (AA2MM) for coarse-grained modeling of vWF that accurately represents the force-based probabilistic change between the unfolded/refolded states. A system of springs is employed to mimic the complex mechanical response of vWF monomers subject to pulling forces. AA2MM was validated by comparing monomer scale simulation results to data from prior pulling experiments on vWF monomer fragments. The model was further validated by comparing multimer scale Brownian dynamics simulation results to experiments using microfluidic chamber microscopy to visualize tethered vWF proteins subject to flow. The A2 domain unfolding reaction was studied in bulk flow simulations (pure shear and elongation flow), giving evidence that elongational flow drives the vWF size regulation process in blood. The mechanoreactive, coarse-grained AA2MM accurately describes the complex mechanical coupling between human blood flow conditions and vWF protein reactivity.