Molecular Dynamics-Markov State Model of Protein Ligand Binding and Allostery in CRIB-PDZ: Conformational Selection and Induced Fit (original) (raw)
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Distinct Roles for Conformational Dynamics in Protein-Ligand Interactions
Structure (London, England : 1993), 2016
Conformational dynamics has an established role in enzyme catalysis, but its contribution to ligand binding and specificity is largely unexplored. Here we used the Tiam1 PDZ domain and an engineered variant (QM PDZ) with broadened specificity to investigate the role of structure and conformational dynamics in molecular recognition. Crystal structures of the QM PDZ domain both free and bound to ligands showed structural features central to binding (enthalpy), while nuclear-magnetic-resonance-based methyl relaxation experiments and isothermal titration calorimetry revealed that conformational entropy contributes to affinity. In addition to motions relevant to thermodynamics, slower microsecond to millisecond switching was prevalent in the QM PDZ ligand-binding site consistent with a role in ligand specificity. Our data indicate that conformational dynamics plays distinct and fundamental roles in tuning the affinity (conformational entropy) and specificity (excited-state conformations)...
The Journal of Chemical Physics, 2015
The native state of a protein consists of an equilibrium of conformational states on an energy landscape rather than existing as a single static state. The coexistence of conformers with different ligand-affinities in a dynamical equilibrium is the basis for the conformational selection model for ligand binding. In this context, the development of theoretical methods that allow us to analyze not only the structural changes but also changes in the fluctuation patterns between conformers will contribute to elucidate the differential properties acquired upon ligand binding. Molecular dynamics simulations can provide the required information to explore these features. Its use in combination with subsequent essential dynamics analysis allows separating large concerted conformational rearrangements from irrelevant fluctuations. We present a novel procedure to define the size and composition of essential dynamics subspaces associated with ligand-bound and ligand-free conformations. These definitions allow us to compare essential dynamics subspaces between different conformers. Our procedure attempts to emphasize the main similarities and differences between the different essential dynamics in an unbiased way. Essential dynamics subspaces associated to conformational transitions can also be analyzed. As a test case, we study the glutaminase interacting protein (GIP), composed of a single PDZ domain. Both GIP ligand-free state and glutaminase L peptide-bound states are analyzed. Our findings concerning the relative changes in the flexibility pattern upon binding are in good agreement with experimental Nuclear Magnetic Resonance data.
Journal of chemical theory and computation, 2016
The binding of a ligand to a protein may induce long-range structural or dynamical changes in the biomacromolecule even at sites physically well separated from the binding pocket. A system for which such behavior has been widely discussed is the PDZ2 domain of human tyrosine phosphatase 1E. Here, we present results from equilibrium trajectories of the PDZ2 domain in the free and ligand-bound state, as well as nonequilibrium simulations of the relaxation of PDZ2 after removal of its peptide ligand. The study reveals changes in inter-residue contacts, backbone dihedral angles, and Cα positions upon ligand release. Our findings show a long-range conformational response of the PDZ2 domain to ligand release in the form of a collective shift of the secondary structure elements α2, β2, β3, α1-β4, and the C terminal loop relative to the rest of the protein away from the N-terminus, and a shift of the loops β2-β3 and β1-β2 in the opposite direction. The shifts lead to conformational changes ...
Conformational Dynamics and Ligand Binding in the Multi-Domain Protein PDC109
PLoS ONE, 2010
PDC109 is a modular multi-domain protein with two fibronectin type II (Fn2) repeats joined by a linker. It plays a major role in bull sperm binding to the oviductal epithelium through its interactions with phosphorylcholines (PhCs), a head group of sperm cell membrane lipids. The crystal structure of the PDC109-PhC complex shows that each PhC binds to the corresponding Fn2 domain, while the two domains are on the same face of the protein. Long timescale explicit solvent molecular dynamics (MD) simulations of PDC109, in the presence and absence of PhC, suggest that PhC binding strongly correlates with the relative orientation of choline-phospholipid binding sites of the two Fn2 domains; unless the two domains tightly bind PhCs, they tend to change their relative orientation by deforming the flexible linker. The effective PDC109-PhC association constant of 28 M {1 , estimated from their potential of mean force is consistent with the experimental result. Principal component analysis of the long timescale MD simulations was compared to the significantly less expensive normal mode analysis of minimized structures. The comparison indicates that difference between relative domain motions of PDC109 with bound and unbound PhC is captured by the first principal component in the principal component analysis as well as the three lowest normal modes in the normal mode analysis. The present study illustrates the use of detailed MD simulations to clarify the energetics of specific ligand-domain interactions revealed by a static crystallographic model, as well as their influence on relative domain motions in a multi-domain protein.
Trends in Biochemical Sciences, 2010
Single molecule and NMR measurements of protein dynamics increasingly uncover the complexity of binding scenarios. Here we describe an extended conformational selection model which embraces a repertoire of selection and adjustment processes. Induced fit can be viewed as a subset of this repertoire, whose contribution is affected by the bondtypes stabilizing the interaction and the differences between the interacting partners. We argue that protein segments whose dynamics are distinct from the rest of the protein ('discrete breathers') can govern conformational transitions and allosteric propagation that accompany binding processes, and as such may be more sensitive to mutational events. Additionally, we highlight the dynamic complexity of binding scenarios as they relate to events such as aggregation and signalling, and the crowded cellular environment.
Nontargeted parallel cascade selection molecular dynamics (nt-PaCS-MD) is proposed as an efficient conformational sampling method to enhance the conformational transitions of proteins, which is an extension of the original targeted PaCS-MD (t-PaCS-MD). The original PaCS-MD comprises cycles of (i) selection of initial structures for multiple independent MD simulations toward a predetermined target and (ii) conformational sampling by the independent MDs. In nt-PaCS-MD, structures that significantly deviate from an average are regarded as candidates that have high potential to address other metastable states and are chosen as the initial structures in the selection. To select significantly deviated structures, we examine the root-mean-square deviation (RMSD) of snapshots generated from the average structure based on Gram−Schmidt othogonalization. nt-PaCS-MD was applied to the folding of the mini-protein chignolin in implicit solvent and to the open−closed conformational transitions of T4 lysozyme (T4L) and glutamine binding protein (QBP) in explicit solvent. We show that nt-PaCS-MD can reach chignolin’s native state and can also cause the open−closed transition of T4L and QBP on a nanosecond time scale, which are very efficient in terms of conformational sampling and comparable to that with t-PaCS-MD
Molecular dynamics of conformational substates for a simplified protein model
The Journal of Chemical Physics, 1994
Extended molecular dynamics simulations covering a total of 0:232 s have been carried out on a simpli ed protein model. Despite its simpli ed structure, that model exhibits properties similar to those of more realistic protein models. In particular, the model was found to undergo transitions between conformational substates at a time scale of several hundred picoseconds. The computed trajectories turned out to be su ciently long as to permit a statistical analysis of that conformational dynamics.
A statistical mechanics handbook for protein-ligand binding simulation
Frontiers in Bioscience, 2013
Introduction 3. Basics 3.1. Fixed energy systems 3.2. Microscopic versus thermodynamic description 3.3. Fixed temperature systems 3.3.1. Consequences of the Boltzmann distribution 3.3.2. Time evolution in the canonical ensemble 3.4. From microscopic quantities to macroscopic observables 3.5. Complementary material to section 3 3.5.1. Derivation of Boltzmann distribution for the canonical ensemble 3.5.2. The Fokker-Plank equation 4. Tools and concepts for the description of the binding process 4.1. Role of the free energy and of the internal constraint 4.1.1. Obstacles to absolute free energy calculation 4.1.2. Free energy differences calculation 4.2. Free energy profiles and reaction paths 4.3. The definition of bound and unbound states and the reaction coordinate 4.4. Potential versus free energy surface 4.5. A didactic example 4.6. Volumetric effect on the unbound state 4.7. Complementary material to section 4 4.7.1. The zero temperature limit for free energy 5. Conclusions 6. Acknowledgements 7. References
Nonequilibrium Modeling of the Elementary Step in PDZ3 Allosteric Communication
The Journal of Physical Chemistry Letters
While allostery is of paramount importance for protein signaling and regulation, the underlying dynamical process of allosteric communication is not well understood. PDZ3 domain represents a prime example of an allosteric single-domain protein, as it features a well-established long-range coupling between the C-terminal α 3-helix and ligand binding. In an intriguing experiment, Hamm and coworkers employed photoswitching of the α 3-helix to initiate a conformational change of PDZ3 that propagates from the C-terminus to the bound ligand within 200 ns. Performing extensive nonequilibrium molecular dynamics simulations, the modeling of the experiment reproduces the measured timescales and reveals a detailed picture of the allosteric communication in PDZ3. In particular, a correlation analysis identifies a network of contacts connecting the α 3-helix and the core of the protein, which move in a concerted manner. Representing a one-step process and involving direct α 3-ligand contacts, this cooperative transition is considered as elementary step in the propagation of conformational change.