Dynamically Driven Allostery in MHC Proteins: Peptide-Dependent Tuning of Class I MHC Global Flexibility

T cell receptor (TCR) recognition of antigenic peptides bound and presented by class I major histocompatibility complex (MHC) proteins underlies the cytotoxic immune response to diseased cells. Crystallographic structures of TCR-peptide/MHC complexes have demonstrated how TCRs simultaneously interact with both the peptide and the MHC protein. However, it is increasingly recognized that, beyond serving as a static platform for peptide presentation, the physical properties of class I MHC proteins are tuned by different peptides in ways that are not always structurally visible. These include MHC protein motions, or dynamics, which are believed to influence interactions with a variety of MHC-binding proteins, including not only TCRs, but other activating and inhibitory receptors as well as components of the peptide loading machinery. Here, we investigated the mechanisms by which peptides tune the dynamics of the common class I MHC protein HLA-A2. By examining more than 50 lengthy molecular dynamics simulations of HLA-A2 presenting different peptides, we identified regions susceptible to dynamic tuning, including regions in the peptide binding domain as well as the distal α3 domain. Further analyses of the simulations illuminated mechanisms by which the influences of different peptides are communicated throughout the protein, and involve regions of the peptide binding groove, the β2-microglobulin subunit, and the α3 domain. Overall, our results demonstrate that the class I MHC protein is a highly tunable peptide sensor whose physical properties vary considerably with bound peptide. Our data provides insight into the underlying principles and suggest a role for dynamically driven allostery in the immunological function of MHC proteins

Vibrational Spectroscopic Map, Vibrational Spectroscopy, and Intermolecular Interaction

© 2020 American Chemical Society. Vibrational spectroscopy is an essential tool in chemical analyses, biological assays, and studies of functional materials. Over the past decade, various coherent nonlinear vibrational spectroscopic techniques have been developed and enabled researchers to study time-correlations of the fluctuating frequencies that are directly related to solute-solvent dynamics, dynamical changes in molecular conformations and local electrostatic environments, chemical and biochemical reactions, protein structural dynamics and functions, characteristic processes of functional materials, and so on. In order to gain incisive and quantitative information on the local electrostatic environment, molecular conformation, protein structure and interprotein contacts, ligand binding kinetics, and electric and optical properties of functional materials, a variety of vibrational probes have been developed and site-specifically incorporated into molecular, biological, and material systems for time-resolved vibrational spectroscopic investigation. However, still, an all-encompassing theory that describes the vibrational solvatochromism, electrochromism, and dynamic fluctuation of vibrational frequencies has not been completely established mainly due to the intrinsic complexity of intermolecular interactions in condensed phases. In particular, the amount of data obtained from the linear and nonlinear vibrational spectroscopic experiments has been rapidly increasing, but the lack of a quantitative method to interpret these measurements has been one major obstacle in broadening the applications of these methods. Among various theoretical models, one of the most successful approaches is a semiempirical model generally referred to as the vibrational spectroscopic map that is based on a rigorous theory of intermolecular interactions. Recently, genetic algorithm, neural network, and machine learning approaches have been applied to the development of vibrational solvatochromism theory. In this review, we provide comprehensive descriptions of the theoretical foundation and various examples showing its extraordinary successes in the interpretations of experimental observations. In addition, a brief introduction to a newly created repository Web site (http://frequencymap.org) for vibrational spectroscopic maps is presented. We anticipate that a combination of the vibrational frequency map approach and state-of-the-art multidimensional vibrational spectroscopy will be one of the most fruitful ways to study the structure and dynamics of chemical, biological, and functional molecular systems in the future

Modeling Carbon Dioxide Vibrational Frequencies in Ionic Liquids: IV. Temperature Dependence

In previous papers in the series, the vibrational spectroscopy of CO2 in ionic liquids (ILs) was investigated at ambient conditions. Here, we extend these studies to understand the temperature dependence of the structure, dynamics, and thermodynamics of CO2 in the 1-butyl-3-methylimidazolium hexafluorophosphate, [bmim]­[PF6], IL. Using spectroscopic mapping techniques, the infrared absorption spectrum of the CO2 asymmetric stretch mode is simulated at a number of temperatures, and the results are found to be consistent with similar experimental studies. Structural correlation functions are used to reveal the thermodynamics of complete CO2 solvent cage breakdown. The enthalpy and entropy of activation for solvent cage reorganization are found to be 6.9 and 7.6 (kcal/mol)/K, respectively, and these values are similar to the those for spectral, orientational, and translational diffusion. Caging times for CO2 are calculated, and it is shown that the short time dynamics of CO2 are unaffected by temperature, even though the long-time dynamics are highly sensitive to temperature

Disparate degrees of hypervariable loop flexibility control T cell receptor cross-reactivity, specificity, and binding mechanism

αβ T cell receptors recognize multiple antigenic peptides bound and presented by major histocompatibility complex molecules. TCR cross-reactivity has been attributed in part to flexibility of the complementarity-determining region loops, yet there have been limited direct studies of loop dynamics to determine the extent of its role. Here we studied the flexibility of the binding loops of the αβ TCR A6 utilizing crystallographic, spectroscopic, and computational methods. A significant role for flexibility in binding and cross-reactivity was indicated only for the CDR3α and CDR3β hypervariable loops. Examination of the energy landscapes of these two loops indicated that CDR3β possesses a broad, smooth landscape, leading to the rapid sampling in the free TCR of a range of conformations compatible with different ligands. The landscape for CDR3α is more rugged, resulting in limited conformational sampling that leads to specificity towards a reduced set of peptides as well as MHC. In addition to informing on the mechanisms of cross-reactivity and specificity, the energy landscapes of the two loops indicate a complex mechanism for TCR binding, incorporating elements of both conformational selection and induced-fit in a manner that blends features of popular models for TCR recognition

Limitations of Time-Resolved Fluorescence Suggested by Molecular Simulations: Assessing the Dynamics of T cell Receptor Binding Loops

AbstractTime-resolved fluorescence anisotropy (TRFA) has a rich history in evaluating protein dynamics. Yet as often employed, TRFA assumes that the motional properties of a covalently tethered fluorescent probe accurately portray the motional properties of the protein backbone at the probe attachment site. In an extensive survey using TRFA to study the dynamics of the binding loops of a αβ T cell receptor, we observed multiple discrepancies between the TRFA data and previously published results that led us to question this assumption. We thus simulated several of the experimentally probed systems using a protocol that permitted accurate determination of probe and protein time correlation functions. We found excellent agreement in the decays of the experimental and simulated correlation functions. However, the motional properties of the probe were poorly correlated with those of the backbone of both the labeled and unlabeled protein. Our results warrant caution in the interpretation of TRFA data and suggest further studies to ascertain the extent to which probe dynamics reflect those of the protein backbone. Meanwhile, the agreement between experiment and computation validates the use of molecular dynamics simulations as an accurate tool for exploring the molecular motion of T cell receptors and their binding loops

Rate and Amplitude Heterogeneity in the Solvation Response of an Ionic Liquid

In contrast with conventional liquids, ionic liquids have solvation dynamics with more rate dispersion and with average times that do not agree with dielectric measurements. A kinetic analog of multidimensional spectroscopy is introduced and used to look for heterogeneity in simulations of coumarin 153 in [Im₁₂]­[BF₄]. Strong heterogeneity is found in the diffusive solvation rate. An unanticipated heterogeneity in the amplitude of the inertial solvation is also seen. Both heterogeneities exchange at the same rate. This rate is similar to the mean diffusive solvation time, putting it in the intermediate-exchange region. Overall, there are multiple violations of the assumptions usually invoked in the theory of reaction dynamics