arXiv subjects

George H. Lorimer

Publications and source records attributed to George H. Lorimer.

4 recordsLinked to original sources

arXiv2022

Friends in need: how chaperonins recognize and remodel proteins that require folding assistance

Chaperonins are biological nanomachines that help newly translated proteins to fold by rescuing them from kinetically trapped misfolded states. Protein folding assistance by the chaperonin machinery is obligatory in vivo for a subset of proteins in the bacterial proteome. Chaperonins are large oligomeric complexes, with unusual seven fold symmetry (group I) or eight/nine fold symmetry (group II), that form double-ring constructs, enclosing a central folding chamber. Dramatic large-scale conformational changes, that take place during ATP-driven cycles, allow chaperonins to bind misfolded proteins, encapsulate them into the expanded cavity and release them back into the cellular environment, regardless of whether they are folded or not. The theory associated with the iterative annealing mechanism, which incorporated the conformational free energy landscape description of protein folding, \textit{quantitatively} explains most, if not all, the available data. Misfolded conformations are associated with low energy minima in a rugged energy landscape. Random disruptions of these low energy conformations result in higher free energy, less folded, conformations that can stochastically partition into the native state. Group I chaperonins (GroEL homologues in eubacteria and endosymbiotic organelles), recognize a large number of misfolded proteins non-specifically and operate through highly coordinated cooperative motions. By contrast, the less well understood group II chaperonins (CCT in Eukarya and thermosome/TF55 in Archaea), assist a selected set of substrate proteins. Chaperonins are implicated in bacterial infection, autoimmune disease, as well as protein aggregation and degradation diseases. Understanding the chaperonin mechanism and their substrates is important not only for the fundamental aspect of cellular protein folding, but also for effective therapeutic strategies.

q-bio.BM↗

arXiv2019

Iterative Annealing Mechanism Explains the Functions of the GroEL and RNA Chaperones

Molecular chaperones are ATP-consuming biological machines, which facilitate the folding of proteins and RNA molecules that are kinetically trapped in misfolded states for long times. Unassisted folding occurs by the kinetic partitioning mechanism according to which folding to the native state, with low probability as well as misfolding to one of the many metastable states, with high probability, occur rapidly on similar time scales. GroEL is an all-purpose stochastic machine that assists misfolded substrate proteins (SPs) to fold. The RNA chaperones (CYT-19) help the folding of ribozymes that readily misfold. GroEL does not interact with the folded proteins but CYT-19 disrupts both the folded and misfolded ribozymes. Despite this major difference, the Iterative Annealing Mechanism (IAM) quantitatively explains all the available experimental data for assisted folding of proteins and ribozymes. Driven by ATP binding and hydrolysis and GroES binding, GroEL undergoes a catalytic cycle during which it samples three allosteric states, referred to as T (apo), R (ATP bound), and R'' (ADP bound). In accord with the IAM predictions, analyses of the experimental data shows that the efficiency of the GroEL-GroES machinery and mutants is determined by the resetting rate $k_{R''\rightarrow T}$, which is largest for the wild type GroEL. Generalized IAM accurately predicts the folding kinetics of Tetrahymena ribozyme and its variants. Chaperones maximize the product of the folding rate and the steady state native state fold by driving the substrates out of equilibrium. Neither the absolute yield nor the folding rate is optimized.

q-bio.BM↗

arXiv2018

Symmetry, Rigidity, and Allosteric Signaling: From Monomeric Proteins to Molecular Machines

Allosteric signaling in biological molecules, which may be viewed as specific action at a distance due to localized perturbation upon binding of ligands or changes in environmental cues, is pervasive in biology. Phenomenological MWC and KNF models galvanized research for over five decades, and these models continue to be the basis for describing the allostery in an array of systems. However, understanding allosteric signaling and the associated dynamics between distinct allosteric states is challenging. In this review, we first describe symmetry and rigidity as essential requirements for allosteric proteins. The general features, with MWC and KNF as two extreme scenarios, emerge when allosteric signaling is viewed from an energy landscape perspective. To go beyond the general theories, we describe computational tools to predict the network of residues that carry allosteric signals. Methods to obtain molecular insights into the dynamics of allosteric transitions are briefly mentioned. The utility of the methods is illustrated by applications to systems ranging from monomeric proteins to multisubunit proteins. Finally, the role allostery plays in the functions of ATP-consuming molecular machines, bacterial chaperonin GroEL and molecular motors, is described. Although universal molecular principles governing allosteric signaling do not exist, we can draw the following general conclusions. (1) Multiple pathways connecting allosteric states are highly heterogeneous. (2) Allosteric signaling is exquisitely sensitive to the architecture of the system, which implies that the capacity for allostery is encoded in the structure itself. (3) The mechanical modes that connect distinct allosteric states are robust to sequence variations. (4) Extensive investigations of allostery in Hemoglobin and more recently GroEL, show that a network of salt-bridge rearrangements serves as allosteric switches.

cond-mat.soft↗

arXiv2006

Dynamics of allosteric transitions in GroEL

The chaperonin GroEL-GroES, a machine which helps some proteins to fold, cycles through a number of allosteric states, the $T$ state, with high affinity for substrate proteins (SPs), the ATP-bound $R$ state, and the $R^{\prime\prime}$ ($GroEL-ADP-GroES$) complex. Structures are known for each of these states. Here, we use a self-organized polymer (SOP) model for the GroEL allosteric states and a general structure-based technique to simulate the dynamics of allosteric transitions in two subunits of GroEL and the heptamer. The $T \to R$ transition, in which the apical domains undergo counter-clockwise motion, is mediated by a multiple salt-bridge switch mechanism, in which a series of salt-bridges break and form. The initial event in the $R \to R^{\prime\prime}$ transition, during which GroEL rotates clockwise, involves a spectacular outside-in movement of helices K and L that results in K80-D359 salt-bridge formation. In both the transitions there is considerable heterogeneity in the transition pathways. The transition state ensembles (TSEs) connecting the $T$, $R$, and $R^{\prime\prime}$ states are broad with the the TSE for the $T \to R$ transition being more plastic than the $R\to R^{\prime\prime}$ TSE. The results suggest that GroEL functions as a force-transmitting device in which forces of about (5-30) pN may act on the SP during the reaction cycle.

q-bio.BM↗