Ligand-Induced Protein Responses and Mechanical Signal Propagation Described by Linear Response Theories

Abstract

In this study, a general linear response theory (LRT) is formulated to describe time-dependent and -independent protein conformational changes upon CO binding with myoglobin. Using the theory, we are able to monitor protein relaxation in two stages. The slower relaxation is found to occur from 4.4 to 81.2 picoseconds and the time constants characterized for a couple of aromatic residues agree with those observed by UV Resonance Raman (UVRR) spectrometry and time resolved x-ray crystallography. The faster "early responses", triggered as early as 400 femtoseconds, can be best described by the theory when impulse forces are used. The newly formulated theory describes the mechanical propagation following ligand-binding as a function of time, space and types of the perturbation forces. The "disseminators", defined as the residues that propagate signals throughout the molecule the fastest among all the residues in protein when perturbed, are found evolutionarily conserved and the mutations of which have been shown to largely change the CO rebinding kinetics in myoglobin.

A computational model for controlling conformational cooperativity and function in proteins

“…This form of the LRT is useful for predicting structural changes teins upon ligand binding. 24 Tamura and Hayashi used molecular dynamics data with LRT to determine global conformational changes upon ligand binding. 25 Hirata developed an LRT to study the structural dynamics of perturbed proteins.…”

“…steric interaction regions: (i) between the helix and the tail (residues 23-35 and 74-77) and (ii) the helix and the N-terminal beta strand (residues 1-11 and[23][24][25][26][27][28][29][30][31][32][33][34][35]. Although allosteric interactions between these regions are not yet identified, there are hints from NMR spectroscopy that points to possible interaction36 : residues Lys11, Lys29, and Lys33, each of which is in one of the proposed allosteric interaction regions show order parameter peaks.…”

Time-Resolved Resonance Raman Spectroscopy and Application to Studies on Ultrafast Protein Dynamics

“…59 Yang et al formulated a general linear response theory to address the physical nature of protein conformational changes. 60 Inspired by our UVRR study, they applied the theory to calculations of the Mb protein response to CO dissociation. Their calculations demonstrated that the theory agreed well with the primary protein changes revealed by our measurements.…”

“…Their calculations demonstrated that the theory agreed well with the primary protein changes revealed by our measurements. 60 …”

“…180,181 Data related to ultrafast protein responses contribute to verification of the linear response approach. An example was demonstrated by observation 50 and calculation 60 on primary protein responses upon CO dissociation (Section 3.1.1). Finally, the validity of the modal description of protein responses is related to the time scale of vibrational energy relaxation.…”