Enzymatic reaction dynamics
Dissecting the Dynamics during Enzyme Catalysis: A Case Study of Pin1 Peptidyl-Prolyl Isomerase
Free energy surfaces have played a central role in studying protein
conformational changes and enzymatic reactions over decades.
Yet, free energy barriers and kinetics are highly dependent on
the coordinates chosen to define the surface, and furthermore,
the dynamics during the reactions are often overlooked.
Our recent study on the Pin1-catalyzed isomerization reaction
has indicated that the isomerization transition events remarkably
deviate from the free energy path, highlighting the need
to understand the reaction dynamics in more detail.
To this end, here we investigate the reaction coordinates that
describe the transition states of the free energy and transition
pathways by minimizing the cross-entropy function. We show that
the isomerization transition events can be expressed by
the concerted changes in the improper torsion angle ζ and
nearby backbone torsional angles of the ligand,
whereas the transition state of the free energy surface involves
changes in a broad range of coordinates including multiple
protein–ligand interactions. The current result supports
the previous finding that the isomerization transitions occur
quickly from the conformational excited states, which is
in sharp contrast to the slow and collective changes suggested
from the free energy path. Our results further indicate that
the coordinates derived from the transition trajectories are
not sufficient for finding the transition states on the free
energy surfaces due to the lack of information from conformational excited states.
Mori & Saito, J.Chem.Theo.COmput. (2020).
Conformational Excitation and Nonequilibrium Transition Facilitate Enzymatic Reactions: Application to Pin1 Peptidyl−Prolyl Isomerase
Conformational flexibility of protein is essential for enzyme catalysis.
Yet, how protein’s conformational rearrangements and dynamics contribute
to catalysis remains highly controversial. To unravel protein’s role in
catalysis, it is inevitable to understand the static and dynamic mechanisms
simultaneously. To this end, here the Pin1-catalyzed isomerization reaction
is studied from the two perspectives. The static view indicates that
the hydrogen bonds involving Pin1 rearrange in a tightly coupled manner
with isomerization. In sharp contrast, the isomerization dynamics are found
to be very rapid; protein’s slow conformational rearrangements thus cannot
occur simultaneously with isomerization, and the reaction proceeds in
a nonequilibrium manner. The distinctive protein conformations necessary
to stabilize the transition state are prepared a priori, i.e.,
as conformational excited states. The present result suggests that
enzymatic reaction is not a simple thermal activation from equilibrium
directly to the transition state, thus adding a novel perspective
to Pauling’s view.
Mori & Saito, J.Phys.Chem.Lett. (2019).