Automated Prediction of Protein Association Rate Constants

Qin, Sanbo; Pang, Xiaodong; Zhou, Huan‐Xiang

doi:10.1016/j.str.2011.10.015

Cited by 110 publications

(240 citation statements)

References 39 publications

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“…4, indicating no route from UB-F state to B-F state). This can be explained by considering that the rigidity of a fully folded α-MoRE disfavors rapid binding by dramatically reducing the association rate constants because of the severe orientational restraints (74). Our theoretical results support a scenario in which disorder facilitates binding.…”

Section: Discussionsupporting

confidence: 64%

Multiscaled exploration of coupled folding and binding of an intrinsically disordered molecular recognition element in measles virus nucleoprotein

Wang

Chu

Longhi

et al. 2013

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

108

119

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Numerous relatively short regions within intrinsically disordered proteins (IDPs) serve as molecular recognition elements (MoREs). They fold into ordered structures upon binding to their partner molecules. Currently, there is still a lack of in-depth understanding of how coupled binding and folding occurs in MoREs. Here, we quantified the unbound ensembles of the α-MoRE within the intrinsically disordered C-terminal domain of the measles virus nucleoprotein. We developed a multiscaled approach by combining a physics-based and an atomic hybrid model to decipher the mechanism by which the α-MoRE interacts with the X domain of the measles virus phosphoprotein. Our multiscaled approach led to remarkable qualitative and quantitative agreements between the theoretical predictions and experimental results (e.g., chemical shifts). We found that the free α-MoRE rapidly interconverts between multiple discrete partially helical conformations and the unfolded state, in accordance with the experimental observations. We quantified the underlying global folding-binding landscape. This leads to a synergistic mechanism in which the recognition event proceeds via (minor) conformational selection, followed by (major) induced folding. We also provided evidence that the α-MoRE is a compact molten globule-like IDP and behaves as a downhill folder in the induced folding process. We further provided a theoretical explanation for the inherent connections between "downhill folding," "molten globule," and "intrinsic disorder" in IDP-related systems. Particularly, we proposed that binding and unbinding of IDPs proceed in a stepwise way through a "kinetic divide-and-conquer" strategy that confers them high specificity without high affinity. multiscale simulation | hybrid structure-based model | free-energy surface | flexible binding | flexible recognition I ntrinsically disordered proteins (IDPs) are a newly recognized class of naturally abundant, functional proteins that are unable to fold into a well-defined secondary or tertiary structure under physiological conditions of pH and salinity in the absence of a partner (1-3). IDPs perform a wide spectrum of biological functions, often related to molecular recognition, signal transduction, and cell regulation (4). In contrast, canonical proteins with ordered structure mainly carry out their functions in catalysis and membrane transport (5). The functional repertoire of ordered proteins and that of IDPs are complementary to each other (2, 4). Earlier bioinformatics studies predicted that more than 50% of eukaryotic proteins have long disordered regions (1, 6), and the proportion further increases up to 70% in signaling proteins (7). Due to their ubiquitous occurrence in the living world and close relationship with human diseases, IDPs have in recent years become a hot topic in protein science (3,8). One of the most interesting characteristics of IDPs is that they often undergo disorder-to-order transitions upon binding to their partner(s), such as proteins or DNA (9-14), even though some IDP-p...

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Section: Discussionsupporting

confidence: 64%

Multiscaled exploration of coupled folding and binding of an intrinsically disordered molecular recognition element in measles virus nucleoprotein

Wang

Chu

Longhi

et al. 2013

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

108

119

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“…In particular, the program TransComp produces results that are accurate to within 1 order of magnitude. 20 Although this program has been originally designed for folded proteins, it can also generate reasonable predictions for IDPs. 26 We used the selected MD frames as input for the TransComp calculations.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

Role of Electrostatic Interactions in Binding of Peptides and Intrinsically Disordered Proteins to Their Folded Targets. 1. NMR and MD Characterization of the Complex between the c-Crk N-SH3 Domain and the Peptide Sos

et al. 2014

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Intrinsically disordered proteins (IDPs) often rely on electrostatic interactions to bind their structured targets. To obtain insight into the mechanism of formation of the electrostatic encounter complex, we investigated the binding of the peptide Sos (PPPVPPRRRR), which serves as a minimal model for an IDP, to the c-Crk N-terminal SH3 domain. Initially, we measured ¹⁵N relaxation rates at two magnetic field strengths and determined the binding shifts for the complex of Sos with wild-type SH3. We have also recorded a 3 μs molecular dynamics (MD) trajectory of this complex using the Amber ff99SB*-ILDN force field. The comparison of the experimental and simulated data shows that MD simulation consistently overestimates the strength of salt bridge interactions at the binding interface. The series of simulations using other advanced force fields also failed to produce any satisfactory results. To address this issue, we have devised an empirical correction to the Amber ff99SB*-ILDN force field whereby the Lennard-Jones equilibrium distance for the nitrogen-oxygen pair across the Arg-to-Asp and Arg-to-Glu salt bridges has been increased by 3%. Implementing this correction resulted in a good agreement between the simulations and the experiment. Adjusting the strength of salt bridge interactions removed a certain amount of strain contained in the original MD model, thus improving the binding of the hydrophobic N-terminal portion of the peptide. The arginine-rich C-terminal portion of the peptide, freed from the effect of the overstabilized salt bridges, was found to interconvert more rapidly between its multiple conformational states. The modified MD protocol has also been successfully used to simulate the entire binding process. In doing so, the peptide was initially placed high above the protein surface. It then arrived at the correct bound pose within ∼2 Å of the crystallographic coordinates. This simulation allowed us to analyze the details of the dynamic binding intermediate, i.e., the electrostatic encounter complex. However, an experimental characterization of this transient, weakly populated state remains out of reach. To overcome this problem, we designed the double mutant of c-Crk N-SH3 in which mutations Y186L and W169F abrogate tight Sos binding and shift the equilibrium toward the intermediate state resembling the electrostatic encounter complex. The results of the combined NMR and MD study of this engineered system will be reported in the next part of this paper.

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“…Furthermore, we consider the modification associated to the crowding-induced interaction energy ΔΔG * c between proteins, which can be made specific based on the thermodynamic analysis for the change of free energy ΔG dil→crd i from a dilute solution to a crowded solution for proteins and transient complex, as given by Eq. (13). Finally, we have Eq.…”

Section: Discussionmentioning

confidence: 99%

“…Basically, there is no simple way to determine whether a given protein complex is controlled by diffusion, conformational changes or mixed range. Nevertheless, many experimental [13] observations reveal that in most cases, the conformational rearrangement is fast relative to the dissociation of transient complex (i.e.,…”

Section: Introductionmentioning

confidence: 99%

Effect of crowding on protein-protein association in diffusion-limited regime

Jing

Chen

Zhao

2018

J. Phys.: Conf. Ser.

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Abstract.In the present paper, we establish a theoretical formalism to study the protein-protein association rate in the framework of diffusion-limited theory. To account for the crowding effect due to the presence of polymer, we particularly take into account the deviation of rotational diffusion of proteins from the Stokes-Einstein-Debye relation. Based on fluid mechanics and depletion theory, a new scaling relation for the retardation factor of the rotational diffusion was proposed. Besides, the crowding-induced interaction energy between the proteins has been also properly introduced into the association rate theory. We apply our theory to calculate the association rate constant of proteins β-lactamase and β-lactamase inhibitor protein in poly(ethylene glycol) solutions. Particular attention is paid to the dependence of the association rate constant on the polymer concentration and polymer molecular weight. The deviation from the simple relation based on Stokes-Einstein approximation is well addressed. We find that our theoretical results show good agreements with the experimental data in the whole concentration region, which demonstrates the validity of our theory.

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Automated Prediction of Protein Association Rate Constants

Cited by 110 publications

References 39 publications

Multiscaled exploration of coupled folding and binding of an intrinsically disordered molecular recognition element in measles virus nucleoprotein

Multiscaled exploration of coupled folding and binding of an intrinsically disordered molecular recognition element in measles virus nucleoprotein

Role of Electrostatic Interactions in Binding of Peptides and Intrinsically Disordered Proteins to Their Folded Targets. 1. NMR and MD Characterization of the Complex between the c-Crk N-SH3 Domain and the Peptide Sos

Effect of crowding on protein-protein association in diffusion-limited regime

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