Arjun Valiya Parambathu, David J Rosenman, Sandeep Yadav, Abraham M Lenhoff
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引用次数: 0
Abstract
Concentrated monoclonal antibody (mAb) solutions can allow subcutaneous administration of effective doses of the therapeutic, but for some mAbs this leads to anomalously high viscosities; mAb-mAb association, leading to formation of clusters or gels, is often the driver of such behavior. Statistical mechanical considerations suggest that such association is likely to be dominated by a single binding configuration. In this work we probe the possible molecular origins of this behavior using atomistic molecular simulations of a mAb known to display high viscosity at low salt concentrations. Orientational exploration identified a small number of high-affinity mAb-mAb configurations based on non-electrostatic contributions to the protein interactions, which reflect the geometric complementarity characteristic of biomolecular recognition. Consideration of electrostatic interactions, which account for most salt effects, adds several tens of kT of attraction to select configurations, although there are uncertainties in the electrostatic calculations using the Poisson-Boltzmann approach. The resulting overall attractive energies, greater than 40 kT, support the existence of a single attractive configuration strong enough to form a mAb network at high concentrations. Simulations with increased ionic strength or for small numbers of point mutations predict some but not all observed experimental trends. Independent molecular dynamics (MD) simulations for two select configurations showed partial agreement with the previous results. Overall, while the molecular origin of high viscosity is plausibly due to a single strongly bound configuration, unambiguous identification of this configuration is limited by the numerical accuracy of the underlying calculations.
期刊介绍:
BJ publishes original articles, letters, and perspectives on important problems in modern biophysics. The papers should be written so as to be of interest to a broad community of biophysicists. BJ welcomes experimental studies that employ quantitative physical approaches for the study of biological systems, including or spanning scales from molecule to whole organism. Experimental studies of a purely descriptive or phenomenological nature, with no theoretical or mechanistic underpinning, are not appropriate for publication in BJ. Theoretical studies should offer new insights into the understanding ofexperimental results or suggest new experimentally testable hypotheses. Articles reporting significant methodological or technological advances, which have potential to open new areas of biophysical investigation, are also suitable for publication in BJ. Papers describing improvements in accuracy or speed of existing methods or extra detail within methods described previously are not suitable for BJ.