Coarse-Grained Simulations of Protein-Protein Association: An Energy Landscape Perspective

Ravikumar, Krishnakumar M.; Huang, Wei; Yang, Sichun

doi:10.1016/j.bpj.2012.07.013

Cited by 51 publications

(81 citation statements)

References 68 publications

(77 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Several computational approaches were developed using a structure-based protein model that incorporated the structural flexibility of a protein in the events of coupled folding and binding (13,(24)(25)(26). Others extended this structure-based model approach by introducing a set of experimentally determined structures in the Hamiltonian (27-32) (such as multiple basin structure-based models) or by including additional nonspecific interactions (33) to investigate the transitions between two or more distinct conformations of a protein (e.g., calcium-bound and unbound conformations of CaM; refs. 34,35).…”

Section: +mentioning

confidence: 99%

Protein recognition and selection through conformational and mutually induced fit

Wang

Zhang

Hoffman

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Protein-protein interactions drive most every biological process, but in many instances the domains mediating recognition are disordered. How specificity in binding is attained in the absence of defined structure contrasts with well-established experimental and theoretical work describing ligand binding to protein. The signaling protein calmodulin presents a unique opportunity to investigate mechanisms for target recognition given that it interacts with several hundred different targets. By advancing coarsegrained computer simulations and experimental techniques, mechanistic insights were gained in defining the pathways leading to recognition and in how target selectivity can be achieved at the molecular level. A model requiring mutually induced conformational changes in both calmodulin and target proteins was necessary and broadly informs how proteins can achieve both high affinity and high specificity.coarse-grained molecular simulations | stopped-flow fluorescence techniques | conformational flexibility | hydrophobic motif | calmodulin binding target T he ubiquitous protein calmodulin (CaM) interacts with a vast selection of binding targets (CaMBTs); however, the molecular mechanisms that underlie target selectivity are not known despite an enormous wealth of structural information (1, 2). What emerges from this is the remarkable conformational flexibility of CaM, which exists in highly dynamic structures in the Ca 2+ free and bound forms (3-6) and will adopt distinct conformations when bound to protein targets. These distinct modes of binding are encoded by CaM-recognition motifs of targets that display impressive variability in amino acid sequence and are often partially or largely disordered in the absence of CaM. These data indicate that CaM-CaMBT interactions lie at the opposite end of the spectrum from the classic "lock and key" mechanism (7) initially proposed for rigid ligand binding to proteins, and require adopting more dynamic models, such as induced fit (8) or conformational selection (9). The induced-fit mechanism posits that productive binding occurs because the rigid ligand can alter the conformation of the enzyme, and that the final conformation exists only in the presence of ligand. Conformational selection assumes that the enzyme naturally samples a variety of conformational states and that the ligand binds to one, or a small subset, of these states. However, newer theories-termed extended conformational selection (10), mutually induced fit (11), fly-casting (12), or folding and binding (13, 14)-have begun to integrate molecule dynamics to describe folding and binding involving flexible molecules in protein-protein interactions, especially for the intrinsically disordered proteins (15-17) for which folding and binding are concomitant.The goal of the present study is to provide mechanistic insights at a molecular level into the time-dependent conformational adjustments between CaM and CaMBT for the binding mechanism. Results show that although CaM visits conformations similar to a target-boun...

show abstract

Section: +mentioning

confidence: 99%

Protein recognition and selection through conformational and mutually induced fit

Wang

Zhang

Hoffman

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

show abstract

“…The first component is the electrostatic interaction which was previously used in the Kim-Hummer model [41,42]. The second component is the hydrophobic interaction, which is calculated by summing the hydrophobic scores of all contact residue pairs.…”

Section: Methodsmentioning

confidence: 99%

A Multiscale Computational Model for Simulating the Kinetics of Protein Complex Assembly

Chen

2018

Methods in Molecular Biology

View full text Add to dashboard Cite

Proteins fulfill versatile biological functions by interacting with each other and forming high-order complexes. Although the order in which protein subunits assemble is important for the biological function of their final complex, this kinetic information has received comparatively little attention in recent years. Here we describe a multiscale framework that can be used to simulate the kinetics of protein complex assembly. There are two levels of models in the framework. The structural details of a protein complex are reflected by the residue-based model, while a lower-resolution model uses a rigid-body (RB) representation to simulate the process of complex assembly. These two levels of models are integrated together, so that we are able to provide the kinetic information about complex assembly with both structural details and computational efficiency.

show abstract

“…is the short-range interactions adopted from the previous coarse-grained models (Ravikumar et al 2012). It consists of three individual terms to constrain the virtual bond length between two consecutive Cα atoms, the virtual bond angle and the virtual dihedral to the native structure.…”

Section: Modeling Mechanical Unfolding Of Protein Tertiary Structuresmentioning

confidence: 99%

Study of protein structural deformations under external mechanical perturbations by a coarse-grained simulation method

Chen

Xie

2015

Biomech Model Mechanobiol

View full text Add to dashboard Cite

The mechanical properties of biomolecules play pivotal roles in regulating cellular functions. For instance, extracellular mechanical stimuli are converted to intracellular biochemical activities by membrane receptors and their downstream adaptor proteins during mechanotransduction. In general, proteins favor the conformation with the lowest free energy. External forces modify the energy landscape of proteins and drive them to unfolded or deformed conformations that are of functional relevance. Therefore, the study of the physical properties of proteins under external forces is of fundamental importance to understand their functions in cellular mechanics. Here, a coarse-grained computational model was developed to simulate the unfolding or deformation of proteins under mechanical perturbation. By applying this method to unfolding of previously studied proteins or protein fragments with external forces, we demonstrated that our results are quantitatively comparable to previous experimental or all-atom computational studies. The model was further extended to the problem of elastic deformation of large protein complexes formed between membrane receptors and their ligands. Our studies of binding between T cell receptor (TCR) and major histocompatibility complex (MHC) illustrated that stretching of MHC ligand initially lowers its binding energy with TCR, supporting the recent experimental report that TCR/MHC complex is formed through the catch-bond mechanism. Finally, the method was, for the first time, applied to pulling of an eight-cadherin cluster that was formed by their trans and cis binding interfaces. Our simulation results show that mechanical properties of adherens junctions are functionally important to cell adhesion.

show abstract

Coarse-Grained Simulations of Protein-Protein Association: An Energy Landscape Perspective

Cited by 51 publications

References 68 publications

Protein recognition and selection through conformational and mutually induced fit

Protein recognition and selection through conformational and mutually induced fit

A Multiscale Computational Model for Simulating the Kinetics of Protein Complex Assembly

Study of protein structural deformations under external mechanical perturbations by a coarse-grained simulation method

Contact Info

Product

Resources

About