Accelerating Reaction Rates of Biomolecules by Using Shear Stress in Artificial Capillary Systems.

Tuuli A Hakala,Emma V Yates,Tuomas P J Knowles,Dijana Matak-Vinkovic,Francisco Corzana,Christopher M Dobson,Rodrigo Martínez,Gonçalo J L Bernardes,Pavan K Challa,Zenon Toprakcioglu,Karthik Nadendla

doi:10.1021/jacs.1c03681

Tuuli A Hakala, Emma V Yates + Show 9 more

Open Access

https://doi.org/10.1021/jacs.1c03681

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Abstract

Biomimetics is a design principle within chemistry, biology, and engineering, but chemistry biomimetic approaches have been generally limited to emulating nature’s chemical toolkit while emulation of nature’s physical toolkit has remained largely unexplored. To begin to explore this, we designed biophysically mimetic microfluidic reactors with characteristic length scales and shear stresses observed within capillaries. We modeled the effect of shear with molecular dynamics studies and showed that this induces specific normally buried residues to become solvent accessible. We then showed using kinetics experiments that rates of reaction of these specific residues in fact increase in a shear-dependent fashion. We applied our results in the creation of a new microfluidic approach for the multidimensional study of cysteine biomarkers. Finally, we used our approach to establish dissociation of the therapeutic antibody trastuzumab in a reducing environment. Our results have implications for the efficacy of existing therapeutic antibodies in blood plasma as well as suggesting in general that biophysically mimetic chemistry is exploited in biology and should be explored as a research area.

Highlights

Biomimetics, the emulation of nature’s elements, models, and systems to solve human problems, is a key principle in many scientific fields including chemistry,[1] biology,[2] and engineering.[3]
We study the impacts of this increase in SASA within a microfluidic system we designed to replicate the shear stress that has been measured in human capillaries, providing a minimal model of an artificial capillary
To study the effect that shear stress has on the protein structure at the atomic level, we first accomplished molecular dynamics (MD) simulations that mimic a simple shear flow[24] on several proteins, including albumin (BSA), βLactoglobulin (β-Lac), β-galactosidase (BLG), and a full length IgG antibody (Tras), as show in Figure 1 and Supporting Fig.s 2−5

Summary

■ INTRODUCTION

Biomimetics, the emulation of nature’s elements, models, and systems to solve human problems, is a key principle in many scientific fields including chemistry,[1] biology,[2] and engineering.[3]. Proteins undergo a simple shear flow[24] that causes an increase in friction due to random collisions of the protein with nearby solvent or other solute molecules that exhibit rotational-translational diffusion This computational approach has recently been applied to understand the rheo-NMR experiments performed on several proteins at the atomic level.[24] Alternatively, we perform steered MD simulations (SMD).[25,26] In these calculations, we apply a force to two specific atoms that allows them to move from an initial position, given by the solved X-ray structure, to a position that we choose arbitrarily.[27,28] In all calculations, one of the atoms chosen is the Cα of the cysteine residue or the Cα or a residue in close proximity to it We expect our study to prompt establishment and exploration of biophysically mimetic chemistry, chemical biology, and biochemistry, in which the variety of forces utilized by nature to alter biomolecular behavior can be exploited for human purposes

■ RESULTS AND DISCUSSION

■ CONCLUSION

■ ACKNOWLEDGMENTS

■ REFERENCES