@article {2022|2151, title = {Symmetry-Adapted Restraints for Binding Free Energy Calculations.}, journal = {J Chem Theory Comput}, year = {2022}, month = {2022 Mar 01}, abstract = {

Binding free energy calculations rely critically on a precise definition of the bound state and well-designed ligand restraints to ensure that binding free energy calculations converge rapidly and yield estimates of well-defined thermodynamic quantities. The distance-to-bound-configuration (DBC) is a single variable that can precisely delineate the bound state of a ligand including translational, rotational and conformational degrees of freedom and has been successfully used to capture binding modes with complex geometries. DBC is defined as the root-mean-square deviation (RMSD) of ligand coordinates in the frame of reference of the binding site. In the special case where the ligand features symmetry-equivalent atoms, a standard RMSD arbitrarily distinguishes equivalent poses, mixing equivalent and nonequivalent degrees of freedom, and preventing the precise delineation of the bound state ensemble, which negates the benefits of defining a flat-bottom binding restraint. To remedy this, we introduce a symmetry-adapted DBC coordinate where the RMSD is minimized over permutations of equivalent ligand atoms. This coordinate is implemented in a portable software library, the Collective Variables Module. We tested the approach by computing the absolute binding free energy of benzene to the engineered site of a mutant lysozyme (L99A/M102H) using alchemical free energy perturbation. We found that the symmetry-adapted restraint leads to well-behaved convergence of both the decoupling free energy in the binding site and the restrained free energy in the gas phase, recovering the affinity computed using a classic center-of-mass restraint. Thus, symmetry-adapted DBC seamlessly generalizes the benefits of DBC restraints to the case of symmetric ligands. The underlying symmetric RMSD coordinate can also be used for analyzing or biasing simulations in other contexts than affinity predictions.

}, issn = {1549-9626}, doi = {10.1021/acs.jctc.1c01235}, author = {Ebrahimi, Mina and J{\'e}r{\^o}me H{\'e}nin} } @article {2020|2142, title = {Scalable molecular dynamics on CPU and GPU architectures with NAMD}, journal = {The Journal of Chemical Physics}, volume = {153}, year = {2020}, chapter = {044130}, abstract = {

NAMD is a molecular dynamics program designed for high-performance simulations of very large biological objects on CPU- and GPU-based architectures. NAMD offers scalable performance on petascale parallel supercomputers consisting of hundreds of thousands of cores, as well as on inexpensive commodity clusters commonly found in academic environments. It is written in C++ and leans on Charm++ parallel objects for optimal performance on low-latency architectures. NAMD is a versatile, multipurpose code that gathers state-of-the-art algorithms to carry out simulations in apt thermodynamic ensembles, using the widely popular CHARMM, AMBER, OPLS, and GROMOS biomolecular force fields. Here, we review the main features of NAMD that allow both equilibrium and enhanced-sampling molecular dynamics simulations with numerical efficiency. We describe the underlying concepts utilized by NAMD and their implementation, most notably for handling long-range electrostatics; controlling the temperature, pressure, and pH; applying external potentials on tailored grids; leveraging massively parallel resources in multiple-copy simulations; and hybrid quantum-mechanical/molecular-mechanical descriptions. We detail the variety of options offered by NAMD for enhanced-sampling simulations aimed at determining free-energy differences of either alchemical or geometrical transformations and outline their applicability to specific problems. Last, we discuss the roadmap for the development of NAMD and our current efforts toward achieving optimal performance on GPU-based architectures, for pushing back the limitations that have prevented biologically realistic billion-atom objects to be fruitfully simulated, and for making large-scale simulations less expensive and easier to set up, run, and analyze. NAMD is distributed free of charge with its source code at www.ks.uiuc.edu.

}, keywords = {NAMD}, doi = {10.1063/5.0014475}, url = {https://aip.scitation.org/doi/10.1063/5.0014475}, author = {James Phillips and David Hardy and Julio Maia and John Stone and Joao Ribeiro and Rafael Bernardi and Ronak Buch and Giacomo Fiorin and J{\'e}r{\^o}me H{\'e}nin and Wei Jiang and Ryan McGreevy and Melo, Marcelo Cardoso dos Reis and Brian Radak and Robert Skeel and Abhishek Singharoy and Yi Wang and Benoit Roux and Aleksei Aksimentiev and Zan Luthey-Schulten and Laxmikant Kale and Klaus Schulten and Christophe Chipot and Emad Tajkhorshid} } @article {2018|2059, title = {A Streamlined, General Approach for Computing Ligand Binding Free Energies and Its Application to GPCR-Bound Cholesterol.}, journal = {Journal of Chemical Theory and Computation}, volume = {14}, year = {2018}, pages = {6560{\textendash}6573}, abstract = {

The theory of receptor-ligand binding equilibria has long been well-established in biochemistry, and was primarily constructed to describe dilute aqueous solutions. Accordingly, few computational approaches have been developed for making quantitative predictions of binding probabilities in environments other than dilute isotropic solution. Existing techniques, ranging from simple automated docking procedures to sophisticated thermodynamics-based methods, have been developed with soluble proteins in mind. Biologically and pharmacologically relevant protein-ligand interactions often occur in complex environments, including lamellar phases like membranes and crowded, nondilute solutions. Here, we revisit the theoretical bases of ligand binding equilibria, avoiding overly specific assumptions that are nearly always made when describing receptor-ligand binding. Building on this formalism, we extend the asymptotically exact Alchemical Free Energy Perturbation technique to quantifying occupancies of sites on proteins in a complex bulk, including phase-separated, anisotropic, or nondilute solutions, using a thermodynamically consistent and easily generalized approach that resolves several ambiguities of current frameworks. To incorporate the complex bulk without overcomplicating the overall thermodynamic cycle, we simplify the common approach for ligand restraints by using a single distance-from-bound-configuration (DBC) ligand restraint during AFEP decoupling from protein. DBC restraints should be generalizable to binding modes of most small molecules, even those with strong orientational dependence. We apply this approach to compute the likelihood that membrane cholesterol binds to known crystallographic sites on three GPCRs (β -adrenergic, 5HT-2B, and μ-opioid) at a range of concentrations. Nonideality of cholesterol in a binary cholesterol:phosphatidylcholine (POPC) bilayer is characterized and consistently incorporated into the interpretation. We find that the three sites exhibit very different affinities for cholesterol: The site on the adrenergic receptor is predicted to be high affinity, with 50\% occupancy for 1:10 CHOL:POPC mixtures. The sites on the 5HT-2B and μ-opioid receptor are predicted to be lower affinity, with 50\% occupancy for 1:10 CHOL:POPC and 1:10 CHOL:POPC, respectively. These results could not have been predicted from the crystal structures alone.

}, issn = {1549-9626}, doi = {10.1021/acs.jctc.8b00447}, author = {Salari, Reza and Joseph, Thomas and Lohia, Ruchi and J{\'e}r{\^o}me H{\'e}nin and Brannigan, Grace} } @article {2017|1686, title = {Smoothed biasing forces yield unbiased free energies with the extended-system Adaptive Biasing Force method}, journal = {J. Phys. Chem. B}, volume = {121}, year = {2017}, month = {dec}, pages = {3676{\textendash}3685}, doi = {10.1021/acs.jpcb.6b10055}, author = {Lesage, A. and Leli{\`e}vre, T. and Stoltz, G. and J{\'e}r{\^o}me H{\'e}nin} } @article {2010|1789, title = {Single-spanning transmembrane domains in cell growth and cell-cell interactions: More than meets the eye?}, journal = {Cell Adh. Migr.}, volume = {4}, number = {2}, year = {2010}, month = {apr}, pages = {313{\textendash}324}, abstract = {

As a whole, integral membrane proteins represent about one third of sequenced genomes, and more than 50\% of currently available drugs target membrane proteins, often cell surface receptors. Some membrane protein classes, with a defined number of transmembrane (TM) helices, are receiving much attention because of their great functional and pharmacological importance, such as G protein-coupled receptors possessing 7 TM segments. Although they represent roughly half of all membrane proteins, bitopic proteins (with only 1 TM helix) have so far been less well characterized. Though they include many essential families of receptors, such as adhesion molecules and receptor tyrosine kinases, many of which are excellent targets for biopharmaceuticals (peptides, antibodies, et al.). A growing body of evidence suggests a major role for interactions between TM domains of these receptors in signaling, through homo and heteromeric associations, conformational changes, assembly of signaling platforms, etc. Significantly, mutations within single domains are frequent in human disease, such as cancer or developmental disorders. This review attempts to give an overview of current knowledge about these interactions, from structural data to therapeutic perspectives, focusing on bitopic proteins involved in cell signaling.

}, keywords = {Animals, Biological, Humans, Membrane Proteins, Models, Protein Structure, Secondary, Signal Transduction, Tertiary}, issn = {1933-6926}, doi = {10.4161/cam.4.2.12430}, author = {Pierre Hubert and Paul Sawma and Jean-Pierre Duneau and Jonathan Khao and J{\'e}r{\^o}me H{\'e}nin and Dominique Bagnard and James Sturgis} }