Temperature Dependence of Thermal Conductivity of Proteins: Contributions of Thermal Expansion and Grüneisen Parameter.

The thermal conductivity of many materials depends on temperature due to several factors, including variation of heat capacity with temperature, changes in vibrational dynamics with temperature, and change in volume with temperature. For proteins some, but not all, of these influences on the variation of thermal conductivity with temperature have been investigated in the past. In this study, we examine the influence of change in volume, and corresponding changes in vibrational dynamics, on the temperature dependence of the thermal conductivity.

A Strategy for Modeling Nonstatistical Reactivity Effects: Combining Chemical Activation Estimates with a Vibrational Relaxation Model.

The kinetics of many chemical reactions can be readily explained with a statistical approach, for example, using a form of transition state theory and comparing calculated Gibbs energies along the reaction coordinate(s). However, there are cases where this approach fails, notably when the vibrational relaxation of the molecule to its statistical equilibrium occurs on the same time scale as the reaction dynamics, whether it is caused by slow relaxation, a fast reaction, or both. These nonstatistical phenomena are then often explored computationally using (quasi)classical ab initio molecular dynamics by calculating a large number of trajectories while being prone to issues such as zero-point energy leakage.

Vibrational Energy Landscapes and Energy Flow in GPCRs.

We construct and analyze disconnectivity graphs to provide the first graphical representation of the vibrational energy landscape of a protein, in this study βAR, a G-protein coupled receptor (GPCR), in active and inactive states. The graphs, which indicate the relative free energy of each residue and the minimum free energy barriers for energy transfer between them, reveal important composition, structural and dynamic properties that mediate the flow of energy. Prolines and glycines, which contribute to GPCR plasticity and function, are identified as bottlenecks to energy transport along the backbone from which alternative pathways for energy transport via nearby noncovalent contacts emerge, seen also in the analysis of first passage time (FPT) distributions presented here.

Dynamics of Hydrogen Bonds between Water and Intrinsically Disordered and Structured Regions of Proteins.

Recent studies indicate more restricted dynamics of water around intrinsically disordered proteins (IDPs) than structured proteins. We examine here the dynamics of hydrogen bonds between water molecules and two proteins, small ubiquitin-related modifier-1 (SUMO-1) and ubiquitin-conjugating enzyme E2I (UBC9), which we compare around intrinsically disordered regions (IDRs) and structured regions of these proteins. It has been recognized since some time that excluded volume effects, which influence access of water molecules to hydrogen-bonding sites, and the strength of hydrogen bonds between water and protein affect hydrogen bond lifetimes.

Locating dynamic contributions to allostery via determining rates of vibrational energy transfer.

Determining rates of energy transfer across non-covalent contacts for different states of a protein can provide information about dynamic and associated entropy changes during transitions between states. We investigate the relationship between rates of energy transfer across polar and nonpolar contacts and contact dynamics for the β-adrenergic receptor, a rhodopsin-like G-protein coupled receptor, in an antagonist-bound inactive state and agonist-bound active state. From structures sampled during molecular dynamics (MD) simulations, we find the active state to have, on average, a lower packing density, corresponding to generally more flexibility and greater entropy than the inactive state.

Energy Transport in Class B GPCRs: Role of Protein-Water Dynamics and Activation.

We compute energy exchange networks (EENs) through glucagon-like peptide-1 receptor (GLP-1R), a class B G-protein-coupled receptor (GPCR), in inactive and two active states, one activated by a peptide ligand and the other by a small molecule agonist, from results of molecular dynamics simulations. The reorganized network upon activation contains contributions from structural as well as from dynamic changes and corresponding entropic contributions to the free energy of activation, which are estimated in terms of the change in rates of energy transfer across non-covalent contacts. The role of water in the EENs and in activation of GLP-1R is also investigated.

A Statistical Journey through the Topological Determinants of the β2 Adrenergic Receptor Dynamics.

Activation of G-protein-coupled receptors (GPCRs) is mediated by molecular switches throughout the transmembrane region of the receptor. In this work, we continued along the path of a previous computational study wherein energy transport in the β2 Adrenergic Receptor (β2-AR) was examined and allosteric switches were identified in the molecular structure through the reorganization of energy transport networks during activation. In this work, we further investigated the allosteric properties of β2-AR, using Protein Contact Networks (PCNs).

Biophysical Insight into the SARS-CoV2 Spike-ACE2 Interaction and Its Modulation by Hepcidin through a Multifaceted Computational Approach.

At the center of the SARS-CoV2 infection, the spike protein and its interaction with the human receptor ACE2 play a central role in the molecular machinery of SARS-CoV2 infection of human cells. Vaccine therapies are a valuable barrier to the worst effects of the virus and to its diffusion, but the need of purposed drugs is emerging as a core target of the fight against COVID19. In this respect, the repurposing of drugs has already led to discovery of drugs thought to reduce the effects of the cytokine storm, but still a drug targeting the spike protein, in the infection stage, is missing.

Enhanced Mobility during Diels-Alder Reaction: Results of Molecular Simulations.

Recent measurements indicate enhanced mobility of solvent molecules during Diels-Alder (DA) and other common chemical reactions. We present results of molecular dynamics simulations of the last stages of the DA cycloaddition reaction, from the transition state configuration to product, of furfurylamine and maleimide in acetonitrile at reactant concentrations studied experimentally. We find enhanced mobility of solvent and reactant molecules up to at least a nanometer from the DA product over hundreds of picoseconds.

The origin and impact of bound water around intrinsically disordered proteins.

Proteins and water couple dynamically over a wide range of time scales. Motivated by their central role in protein function, protein-water dynamics and thermodynamics have been extensively studied for structured proteins, where correspondence to structural features has been made. However, properties controlling intrinsically disordered protein (IDP)-water dynamics are not yet known.

Electric Fields Influence Intramolecular Vibrational Energy Relaxation and Line Widths.

Intramolecular vibrational energy relaxation (IVR) is fundamentally important to chemical dynamics. We show that externally applied electric fields affect IVR and vibrational line widths by changing the anharmonic couplings and frequency detunings between modes. We demonstrate this effect in benzonitrile for which prior experimental results show a decrease in vibrational line width as a function of applied electric field.

Activation-Induced Reorganization of Energy Transport Networks in the β Adrenergic Receptor.

We compute energy exchange networks (EENs) through the β adrenergic receptor (βAR), a G-protein coupled receptor (GPCR), in inactive and active states, based on the results of molecular dynamics simulations of this membrane bound protein. We introduce a new definition for the reorganization of EENs upon activation that depends on the relative change in rates of energy transfer across noncovalent contacts throughout the protein. On the basis of the reorganized network that we obtain for βAR upon activation, we identify a branched pathway between the agonist binding site and the cytoplasmic region, where a G-protein binds to the receptor when activated.

Change in vibrational entropy with change in protein volume estimated with mode Grüneisen parameters.

For a small adjustment in average volume, due to a change in state of a protein or other macromolecule at constant temperature, the change in vibrational entropy is related to the mode Grüneisen parameters, which relate shifts in frequency to a small volume change. We report here values of mode Grüneisen parameters computed for two hydrated proteins, cytochrome c and myoglobin, which exhibit trends with mode frequency resembling those of glassy systems. We use the mode Grüneisen parameters to relate volumetric thermal expansion to previously computed values of the isothermal compressibility for several proteins.

Locating and Navigating Energy Transport Networks in Proteins.

We review computational methods to locate energy transport networks in proteins that are based on the calculation of local energy diffusion in nanoscale systems. As an illustrative example, we discuss energy transport networks computed for the homodimeric hemoglobin from Scapharca inaequivalvis, where channels for facile energy transport, which include the cluster of water molecules at the interface of the globules, have been found to lie along pathways that experiments reveal are important in allosteric processes. We also review recent work on master equation simulations to model energy transport dynamics, including efforts to relate rate constants in the master equation to protein structural dynamics.

Energy Transfer across Nonpolar and Polar Contacts in Proteins: Role of Contact Fluctuations.

Molecular dynamics simulations of the villin headpiece subdomain HP36 have been carried out to examine relations between rates of vibrational energy transfer across non-covalently bonded contacts and equilibrium structural fluctuations, with focus on van der Waals contacts. Rates of energy transfer across van der Waals contacts vary inversely with the variance of the contact length, with the same constant of proportionality for all nonpolar contacts of HP36. A similar relation is observed for hydrogen bonds, but the proportionality depends on contact pairs, with hydrogen bonds stabilizing the α-helices all exhibiting the same constant of proportionality, one that is distinct from those computed for other polar contacts.

Water-mediated biomolecular dynamics and allostery.

Dynamic coupling with water contributes to regulating the functional dynamics of a biomolecule. We discuss protein-water dynamics, with emphasis on water that is partially confined, and the role of protein-confined water dynamics in allosteric regulation. These properties are illustrated with two systems, a homodimeric hemoglobin from Scapharca inaequivalvis (HbI) and an A adenosine receptor (AAR).

Recent developments in the computational study of protein structural and vibrational energy dynamics.

Recent developments in the computational study of energy transport in proteins are reviewed, including advances in both methodology and applications. The concept of energy exchange network (EEN) is discussed, and a recent calculation of EENs for the allosteric protein FixL is reviewed, which illustrates how residues and protein regions involved in the allosteric transition can be identified. Recent work has examined relations between EENs and protein dynamics as well as structure.

Variation of Energy Transfer Rates across Protein-Water Contacts with Equilibrium Structural Fluctuations of a Homodimeric Hemoglobin.

Molecular dynamics simulations of the homodimeric hemoglobin from (HbI) have been carried out to examine relations between rates of vibrational energy transfer across nonbonded contacts and equilibrium structural fluctuations, with emphasis on protein-water contacts. The scaling of rates of energy transfer with equilibrium fluctuations of the contact length is found to hold up well for contacts between residues and hemes at the interface and the cluster of 17 interface water molecules in the unliganded state of HbI, as well as for the liganded state, for which the cluster contains on average 11 water molecules. In both states, the rate of energy transfer is also found to satisfy a diffusion relation.

Tuning Molecular Vibrational Energy Flow within an Aromatic Scaffold via Anharmonic Coupling.

From guiding chemical reactivity in synthesis or protein folding to the design of energy diodes, intramolecular vibrational energy redistribution harnesses the power to influence the underlying fundamental principles of chemistry. To evaluate the ability to steer these processes, the mechanism and time scales of intramolecular vibrational energy redistribution through aromatic molecular scaffolds have been assessed by utilizing two-dimensional infrared (2D IR) spectroscopy. 2D IR cross peaks reveal energy relaxation through an aromatic scaffold from the azido- to the cyano-vibrational reporters in -azidobenzonitrile (PAB) and -(azidomethyl)benzonitrile (PAMB) prior to energy relaxation into the solvent.

Energy Transport across Interfaces in Biomolecular Systems.

Energy transport during chemical reactions or following photoexcitation in systems of biological molecules is mediated by numerous interfaces that separate chemical groups and molecules. Describing and predicting energy transport has been complicated by the inhomogeneous environment through which it occurs, and general rules are still lacking. We discuss recent work on identification of networks for vibrational energy transport in biomolecules and their environment, with focus on the nature of energy transfer across interfaces.

Scaling of Rates of Vibrational Energy Transfer in Proteins with Equilibrium Dynamics and Entropy.

Theoretical arguments and results of molecular dynamics (MD) simulations of myoglobin at 300 K are presented to relate rates of vibrational energy transfer across nonbonded contacts interacting via short-range potentials to dynamics of the contact. Both theory and the results of the simulations support a scaling relation between the energy transfer rate and the inverse of the variance in the distance between hydrogen-bonded contacts. The results of the MD simulations do not support such a relation for longer-range charged contacts.

Molecules and the Eigenstate Thermalization Hypothesis.

We review a theory that predicts the onset of thermalization in a quantum mechanical coupled non-linear oscillator system, which models the vibrational degrees of freedom of a molecule. A system of non-linear oscillators perturbed by cubic anharmonic interactions exhibits a many-body localization (MBL) transition in the vibrational state space (VSS) of the molecule. This transition can occur at rather high energy in a sizable molecule because the density of states coupled by cubic anharmonic terms scales as , in marked contrast to the total density of states, which scales as exp(), where is a constant.

Vibrational States and Nitrile Lifetimes of Cyanophenylalanine Isotopomers in Solution.

Nitrile lifetimes and the structure of the vibrational state space of four isotopomers of cyanophenylalanine in solution are calculated. While the frequency of the nitrile of the four isotopomers decreases in the order CN, CN, CN, and CN, the lifetime varies nonmonotonically with the change in frequency. The vibrational properties of the molecules that control the lifetime are examined.