Energy flow and intersubunit signalling in GSAM: A non-equilibrium molecular dynamics study

Abstract

Graphical abstract The identification of discrete subsets of residues which respond to a local injection of thermal energy into the catalytic intermediates or cofactors within the active sites of GSAM, using non-equilibrium MD simulations of thermal diffusion, shows that the architecture of GSAM potentially supports a number of specific pathways for the flow of vibrational energy within and between the two subunits of the enzyme. Assuming that the thermal excitation with a heat bath acts as a physical proxy for chemical activity, these pathways may form the basis of a communication network for coordinating and triggering allosteric conformational changes in the two subunits by shuttling information about chemical modifications of the catalytic intermediates within the two active sites back and forth between the two subunits.

Along the allostery stream: Recent advances in computational methods for allosteric drug discovery

“…Traditionally, allosteric signals are considered to be "one-way-trips," where perturbations stemming from allosteric sites leverage variations towards the corresponding orthosteric sites, thereby conferring regulatory impacts. 9,29,117,[129][130][131][132] However, with the crosstalk between allosteric and orthosteric sites becomes more and more thoroughly characterized, a novel bidirectional allosteric signaling theory was put forward. In this theory, regulatory signals can not only originate from allosteric sites and head towards orthosteric sites, but also can transduce reversely from orthosteric sites towards allosteric sites.…”

“…Traditionally, allosteric signals are considered to be “one‐way‐trips,” where perturbations stemming from allosteric sites leverage variations towards the corresponding orthosteric sites, thereby conferring regulatory impacts 9,29,117,129–132 . However, with the crosstalk between allosteric and orthosteric sites becomes more and more thoroughly characterized, a novel bidirectional allosteric signaling theory was put forward.…”

Harnessing Reversed Allosteric Communication: A Novel Strategy for Allosteric Drug Discovery

“…Allostery, or allosteric regulation, is a fundamental and common mechanism of intramolecular signal transmission, where the structure and dynamics of orthosteric sites are fine-tuned by local perturbations at other topographically distal sites (defined as allosteric sites) through dynamic effects with the conformational ensembles of biomacromolecules. − Allosteric regulation plays a pivotal role in tweaking a variety of biological processes, such as signal transduction, cellular metabolism, enzyme catalysis, and gene regulation, , and is thus considered the “the second secret of life” . Allosteric drugs possess several significant advantages over traditional orthosteric drugs, including greater selectivity, better physicochemical properties, and lower off-target toxicity, and thus represent a new paradigm for modern innovative drug design. − …”

“…In contrast, extensive and efficient computational approaches have enabled us to overcome the limitations of experimental approaches. Structure-based computational approaches, such as molecular dynamics (MD) simulations, − FPocket (a pocket detection program), and Allosite (a program that uses SVM to predict protein allosteric sites), can predict potential allosteric sites by coupling the conformational and temporal features of protein complexes. Sequence-based computational approaches, such as statistical coupling analysis, can identify residues that act as evolutionary, structural, and functional sectors in a protein by probing the homology of the sequence, , providing ingenious insights into the prediction of allosteric sites.…”

Energy Transfer across Nonpolar and Polar Contacts in Proteins: Role of Contact Fluctuations

“…The study of vibrational energy relaxation in proteins, ,,,− part of a long-standing goal of describing relaxation dynamics in complex molecular environments, − has led to a search for relatively simple models that capture its main features. This has included studies addressing the role of structure and bonding, dynamics, ,,− and quantum mechanical effects. − Coarse-grain modeling using a classical master equation offers a promising approach to model energy transport in proteins and protein complexes, ,, identifying regions along which transport is facile and reproducing energy dynamics quite well when compared with results of all-atom simulations. The master equation simulations support a diffusion-like picture for transport.…”