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2016 ; 120
(33
): 8416-23
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Electrostatic Steering Accelerates C3d:CR2 Association
#MMPMID27092816
Mohan RR
; Huber GA
; Morikis D
J Phys Chem B
2016[Aug]; 120
(33
): 8416-23
PMID27092816
show ga
Electrostatic effects are ubiquitous in protein interactions and are found to be
pervasive in the complement system as well. The interaction between complement
fragment C3d and complement receptor 2 (CR2) has evolved to become a link between
innate and adaptive immunity. Electrostatic interactions have been suggested to
be the driving factor for the association of the C3d:CR2 complex. In this study,
we investigate the effects of ionic strength and mutagenesis on the association
of C3d:CR2 through Brownian dynamics simulations. We demonstrate that the
formation of the C3d:CR2 complex is ionic strength-dependent, suggesting the
presence of long-range electrostatic steering that accelerates the complex
formation. Electrostatic steering occurs through the interaction of an acidic
surface patch in C3d and the positively charged CR2 and is supported by the
effects of mutations within the acidic patch of C3d that slow or diminish
association. Our data are in agreement with previous experimental mutagenesis and
binding studies and computational studies. Although the C3d acidic patch may be
locally destabilizing because of unfavorable Coulombic interactions of like
charges, it contributes to the acceleration of association. Therefore,
acceleration of function through electrostatic steering takes precedence to
stability. The site of interaction between C3d and CR2 has been the target for
delivery of CR2-bound nanoparticle, antibody, and small molecule biomarkers, as
well as potential therapeutics. A detailed knowledge of the physicochemical basis
of C3d:CR2 association may be necessary to accelerate biomarker and drug
discovery efforts.
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