posted on 2024-02-06, 06:05authored byXin-Qiu Yao, Donald Hamelberg
Fully understanding
the mechanism of allosteric regulation in biomolecules
requires separating and examining all of the involved factors. In
enzyme catalysis, allosteric effector binding shifts the structure
and dynamics of the active site, leading to modified energetic (e.g.,
energy barrier) and dynamical (e.g., diffusion coefficient) factors
underlying the catalyzed reaction rate. Such modifications can be
subtle and dependent on the type of allosteric effector, representing
a fine-tuning of protein function. The microscopic description of
allosteric regulation at the level of function-dictating factors has
prospective applications in fundamental and pharmaceutical sciences,
which is, however, largely missing so far. Here, we characterize the
allosteric fine-tuning of enzyme catalysis, using human Pin1 as an
example, by performing more than half-millisecond all-atom molecular
dynamics simulations. Changes of reaction kinetics and the dictating
factors, including the free energy surface along the reaction coordinate
and the diffusion coefficient of the reaction dynamics, under various
enzyme and allosteric effector binding conditions are examined. Our
results suggest equal importance of the energetic and dynamical factors,
both of which can be modulated allosterically, and the combined effect
determines the final allosteric output. We also reveal the potential
dynamic basis for allosteric modulation using an advanced statistical
technique to detect function-related conformational dynamics. Methods
developed in this work can be applied to other allosteric systems.