I would like to express my gratitude to Wonpil Im, Nilesh Banavali, and Yun Luo and all the contributors for this Special Issue of the Journal of Computational Chemistry in celebration of my 60^th birthday. To put it simply, I am very touched by the numerous contributions, and frankly humbled by the scope of the research presented here. Over the years, I had the pleasure and the good chance to cross path with many of these authors, students, postdocs, collaborators, getting a slice of the world as I was working with wonderfully bright people from all continents.

The more I think about this journey, and as Jacques Brel would put it, “Mes souvenir deviennent, ce que les vieux en font…” (Les Marquises 1977), good chance is certainly an undeniably important factor. Clearly, good chance was involved in meeting Rémy Sauvé who introduced me to the fascinating world of patch clamp and single channel recordings, Dennis Salahub who conveyed his passion for quantum chemistry, Martin Zuckermann who communicated his enthusiasm for statistical mechanics, and finally Martin Karplus my Ph.D. thesis advisor who will always be a constant inspiration. Let there be many more years of research and scientific investigations!

Studies of protein conformational change represent a significant challenge to computer simulations, owing to their wide-ranging length and time scales. Enhanced sampling approaches that can converge on the most likely path of change can help describe protein activity. This is illustrated with Roux's “swarms of trajectories” string method, which has been used to solve the allosteric gating mechanisms for a pentameric ligand-gated ion channel, yielding the molecular events, free energies, and kinetics to explain those hidden processes.

Given that the process of protein evolution occurs in an aqueous environment, the inclusion of water molecules in structural and functional adaptation is likely to be a major response to the selection pressures that drive evolution. Conserved water-binding sites retained across the Ras superfamily (shown in the figure) are associated with the common switch mechanism and serve as anchors for water-mediated networks that evolved separately in the Ras, Rho, Rab, and Arf branches.

The double electron–electron resonance (DEER) is a powerful technique in structural biology to obtain distance information two unpaired electron spins. DEER Facilitator in CHARMM-GUIis presented as a new tool that consists of two modules Spin-Pair Distributor and reMD Prepper to setup molecular dynamics simulations that utilize information from DEER experiments.

In the present work, modulation by CO₂ of the membrane permeability to drugs has been investigated combining free energy and diffusivity calculations within the framework of the fractional solubility-diffusion model of permeation. The results indicate that CO₂ loosens the membrane, thereby increasing the permeability to drugs. The present contribution provides a newfangled view that the thermodynamics and kinetics of permeation events can be modulated by gaseous species.

Reactions involving cysteine thiols often involve an anionic thiolate intermediate. Delocalization error in many popular density-functional theory (DFT) methods results in incorrect predictions of thio-Michael addition mechanisms of covalent-modifier drugs, while large exact-exchange components or range-separated functionals address these issues to some degree. Density-Functional Tight-Binding (DFTB) methods also fail to predict a stable enolate, while some semiempirical methods provide qualitative agreement with high-level theory. The thio-Michael additions are found to be an extremely stringent test of electronic structure methods, highlighting the need for accurate treatment of both electron delocalization and nonbonded repulsion.

Cation-π and anion-ring interactions are common in proteins. To improve the accuracy of molecular dynamics simulations, the Drude-2013 polarizable protein force field was optimized targeting QM model compound interaction energies. The resulting force field, Drude-2013-CP, is demonstrated to be capable of reproducing experimentally identified cation-π and anion-ring interactions among multiple protein systems.

A simulation methodology to calculate the potential of mean force of an arbitrary deformation of a lipid bilayer is presented. The membrane need not be homogeneous or symmetric, and lipids might be atomically detailed or coarse-grained. The central element is a grid-based collective variable denominated Multi-Map, which quantifies the membrane similarity to a set of density fields reflecting the transformation of interest. The proposed approach may be adapted to study other solvent reorganization processes.

Using adenosine A₁ receptor (A₁AR) as a model G-protein-coupled receptor (GPCR), Gaussian accelerated molecular dynamics (GaMD) was applied to explore GPCR–membrane interactions. Membrane lipids played a key role in stabilizing different conformational states of the A₁AR. Activation of the A₁AR led to differential dynamics in the upper and lower leaflets of the lipid bilayer. The GaMD simulations revealed strongly coupled dynamics of the GPCR and lipids that depend on the receptor activation state.

Cation–π interactions are important for protein stability and for molecular recognition in general, yet are not always adequately described by molecular mechanics models. The Drude polarizable force field is optimized for the interaction of Li⁺, Na⁺, K⁺, Rb⁺, Cs⁺, NH₄⁺, (CH₃)₄⁺, and (C₂H₅)₄N⁺ with aromatic compounds representing the side chains of Phe, Tyr, and Trp and used to evaluate the stability and geometry of the complexes in water.