Performance and Analysis of the Alchemical Transfer Method for Binding-Free-Energy Predictions of Diverse Ligands.

The Alchemical Transfer Method (ATM) is herein validated against the relative binding-free energies (RBFEs) of a diverse set of protein-ligand complexes. We employed a streamlined setup workflow, a bespoke force field, and AToM-OpenMM software to compute the RBFEs of the benchmark set prepared by Schindler and collaborators at Merck KGaA. This benchmark set includes examples of standard small R-group ligand modifications as well as more challenging scenarios, such as large R-group changes, scaffold hopping, formal charge changes, and charge-shifting transformations. The novel coordinate perturbation scheme and a dual-topology approach of ATM address some of the challenges of single-topology alchemical RBFE methods. Specifically, ATM eliminates the need for splitting electrostatic and Lennard-Jones interactions, atom mapping, defining ligand regions, and postcorrections for charge-changing perturbations. Thus, ATM is simpler and more broadly applicable than conventional alchemical methods, especially for scaffold-hopping and charge-changing transformations. Here, we performed well over 500 RBFE calculations for eight protein targets and found that ATM achieves accuracy comparable to that of existing state-of-the-art methods, albeit with larger statistical fluctuations. We discuss insights into the specific strengths and weaknesses of the ATM method that will inform future deployments. This study confirms that ATM can be applied as a production tool for RBFE predictions across a wide range of perturbation types within a unified, open-source framework.

The slow but steady rise of binding free energy calculations in drug discovery.

Binding free energy calculations are increasingly used in drug discovery research to predict protein-ligand binding affinities and to prioritize candidate drug molecules accordingly. It has taken decades of collective effort to transform this academic concept into a technology adopted by the pharmaceutical and biotech industry. Having personally witnessed and taken part in this transformation, here I recount the (incomplete) list of problems that had to be solved to make this computational tool practical and suggest areas of future development.

Taming multiple binding poses in alchemical binding free energy prediction: the ß-cyclodextrin host-guest SAMPL9 blinded challenge.

We apply the Alchemical Transfer Method (ATM) and a bespoke fixed partial charge force field to the SAMPL9 bCD host-guest binding free energy prediction challenge that comprises a combination of complexes formed between five phenothiazine guests and two cyclodextrin hosts. Multiple chemical forms, competing binding poses, and computational modeling challenges pose significant obstacles to obtaining reliable computational predictions for these systems. The phenothiazine guests exist in solution as racemic mixtures of enantiomers related by nitrogen inversions that bind the hosts in various binding poses, each requiring an individual free energy analysis. Due to the large size of the guests and the conformational reorganization of the hosts, which prevent a direct absolute binding free energy route, binding free energies are obtained by a series of absolute and relative binding alchemical steps for each chemical species in each binding pose. Metadynamics-accelerated conformational sampling was found to be necessary to address the poor convergence of some numerical estimates affected by conformational trapping. Despite these challenges, our blinded predictions quantitatively reproduced the experimental affinities for the ß-cyclodextrin host and, to a lesser extent, those with a methylated derivative. The work illustrates the challenges of obtaining reliable free energy data in in silico drug design for even seemingly simple systems and introduces some of the technologies available to tackle them.

Molecular Latent Space Simulators for Distributed and Multimolecular Trajectories.

All atom molecular dynamics (MD) simulations offer a powerful tool for molecular modeling, but the short time steps required for numerical stability of the integrator place many interesting molecular events out of reach of unbiased simulations. The popular and powerful Markov state modeling (MSM) approach can extend these time scales by stitching together multiple short discontinuous trajectories into a single long-time kinetic model but necessitates a configurational coarse-graining of the phase space that entails a loss of spatial and temporal resolution and an exponential increase in complexity for multimolecular systems. Latent space simulators (LSS) present an alternative formalism that employs a dynamical, as opposed to configurational, coarse graining comprising three back-to-back learning problems to (i) identify the molecular system's slowest dynamical processes, (ii) propagate the microscopic system dynamics within this slow subspace, and (iii) generatively reconstruct the trajectory of the system within the molecular phase space. A trained LSS model can generate temporally and spatially continuous synthetic molecular trajectories at orders of magnitude lower cost than MD to improve sampling of rare transition events and metastable states to reduce statistical uncertainties in thermodynamic and kinetic observables. In this work, we extend the LSS formalism to short discontinuous training trajectories generated by distributed computing and to multimolecular systems without incurring exponential scaling in computational cost. First, we develop a distributed LSS model over thousands of short simulations of a 264-residue proteolysis-targeting chimera (PROTAC) complex to generate ultralong continuous trajectories that identify metastable states and collective variables to inform PROTAC therapeutic design and optimization. Second, we develop a multimolecular LSS architecture to generate physically realistic ultralong trajectories of DNA oligomers that can undergo both duplex hybridization and hairpin folding. These trajectories retain thermodynamic and kinetic characteristics of the training data while providing increased precision of folding populations and time scales across simulation temperature and ion concentration.

Evolution properties of twisted Hermite Gaussian Schell-model beams in non-Kolmogorov turbulence.

A general form of twisted Hermite Gaussian Schell-model (THGSM) beams is introduced; analytical expressionsare obtained for cross-spectral density and M2-factor using the extended Huygens-Fresnel principle and Wigner function. The evolution of THGSM beams during propagation in non-Kolmogorov turbulence is shown numerically; the beams exhibit self-splitting and twist into two lobes. The intensity distribution evolves into a Gaussian shape and beam quality worsens with increasing distance; the intensity distribution and M2-factor are determined by the twist factor, beam orders, and other beam parameters. THGSM beams provide more degrees of freedom to regulate beam parameters, thereby enriching the types of partially coherent beams.

Twisted Gaussian Schell-model breathers and solitons in strongly nonlocal nonlinear media.

Based on the Snyder-Mitchell linear model and the cross-spectral density (CSD) function, the analytical propagation formula of twisted Gaussian Schell-model (TGSM) beams in strongly nonlocal nonlinear medium (SNNM) is derived. Then the propagation characteristics of TGSM beam are studied. It is found that the soliton radius is jointly determined by the initial power, coherence length, and twist factor; the degree of spatial coherence is adjusted by changing the twist factor without affecting the soliton intensity. In the case of non-soliton properties, there is a threshold of coherence length which makes partially coherent beams have the same evolution law as completely coherent beams. Furthermore, increasing the twist factor, decreasing the coherence length and initial power can improve the beam quality of the beam propagating in SNNM.

Superimposed Hermite-Gaussian-correlated Schell-model beam with multiple off-axis vortices.

We first introduce a class of a superimposed Hermite-Gaussian-correlated Schell model with a multiple off-axis vortices beam, with the side lobe of the beam carrying one to four vortex singularities at the source plane. Subsequently, the variation laws of this beam after being focused by a thin lens are studied theoretically to obtain the optimal beam parameters. The numerical simulation results show that the beam possesses a unique multiple vortex structure, phase structure, and orbital angular momentum. Its intensity resembles a spiral staircase rotating around the axes. The rotational symmetry property of the transverse energy flow along the z axis was broken by the vortices. The hot spot position can be adjusted flexibly by changing the off-axis distance of vortices. This study is of great significance for nondestructive capture and manipulation of multiple particles or cells.

ATP-Driven Nonequilibrium Activation of Kinase Clients by the Molecular Chaperone Hsp90.

The molecular chaperone 90-kDa heat-shock protein (Hsp90) assists the late-stage folding and activation of diverse types of protein substrates (called clients), including many kinases. Previous studies have established that the Hsp90 homodimer undergoes an ATP-driven cycle through open and closed conformations. Here, I propose a model of client activation by Hsp90 that predicts that this cycle enables Hsp90 to use ATP energy to drive a client out of thermodynamic equilibrium toward its active conformation. My model assumes that an Hsp90-bound client can transition between a deactivating conformation and an activating conformation. It suggests that the cochaperone Cdc37 aids Hsp90 to activate kinase clients by differentiating between these two intermediate conformations. My model makes experimentally testable predictions, including how modulating the stepwise kinetics of the Hsp90 cycle-for example, by various cochaperones-affects the activation of different clients. My model may inform client-specific and cell-type-specific therapeutic intervention of Hsp90-mediated protein activation.

Shaping the focal intensity distribution using a partially coherent radially polarized beam with multiple off-axis vortices.

A new kind of partially coherent vector vortex beam, namely, the partially coherent radially polarized (PCRP) beam with multiple off-axis vortices, is introduced, and the average intensity distributions of such vortex beam focused by a thin lens are investigated theoretically. It is novelty that the off-axis vortices will induce the focal intensity redistribution and reconstruction, while this remarkable characteristic will be vanished in the case of a very low coherence. In view of this distinctive feature, a new method has been put forward to shape or modulate the focal intensity distribution by elaborately tailoring the multiple off-axis vortices as well as the coherence length. More importantly, some peculiar focal fields with novel structures, such as bar-shaped, triangle-shaped, square-shaped, and pentagon-shaped hollow profiles or flat-top foci, are obtained. Our results indicate that modulating the multiple off-axis vortices provides an additional degree of freedom for focus shaping.

Alchemical Binding Free Energy Calculations in AMBER20: Advances and Best Practices for Drug Discovery.

Predicting protein-ligand binding affinities and the associated thermodynamics of biomolecular recognition is a primary objective of structure-based drug design. Alchemical free energy simulations offer a highly accurate and computationally efficient route to achieving this goal. While the AMBER molecular dynamics package has successfully been used for alchemical free energy simulations in academic research groups for decades, widespread impact in industrial drug discovery settings has been minimal because of the previous limitations within the AMBER alchemical code, coupled with challenges in system setup and postprocessing workflows. Through a close academia-industry collaboration we have addressed many of the previous limitations with an aim to improve accuracy, efficiency, and robustness of alchemical binding free energy simulations in industrial drug discovery applications. Here, we highlight some of the recent advances in AMBER20 with a focus on alchemical binding free energy (BFE) calculations, which are less computationally intensive than alternative binding free energy methods where full binding/unbinding paths are explored. In addition to scientific and technical advances in AMBER20, we also describe the essential practical aspects associated with running relative alchemical BFE calculations, along with recommendations for best practices, highlighting the importance not only of the alchemical simulation code but also the auxiliary functionalities and expertise required to obtain accurate and reliable results. This work is intended to provide a contemporary overview of the scientific, technical, and practical issues associated with running relative BFE simulations in AMBER20, with a focus on real-world drug discovery applications.

Evolution properties of the radially polarized Laguerre-Gaussian-correlated Schell-model beams propagating in uniaxial crystals.

In this paper, we discuss, both analytically and numerically, the paraxial propagation of the radially polarized Laguerre-Gaussian-correlated Schell-model (LGCSM) beams orthogonal to the optical axis in uniaxial crystals. The analytical expression for the cross-spectral density function and the second-order moments of the radially polarized LGCSM beams are derived, and the evolution properties of the normalized intensity distribution, the spectral degree of the coherence (SDOC), and the spectral degree of the polarization (SDOP) in uniaxial crystals are elucidated by numerical examples. It is found that the intensity distribution of the radially polarized LGCSM beams evolves from a doughnut shape into a solid shape and finally converts into an elliptical symmetric hollow-ring profile in uniaxial crystals due to the combined effect of special correlation functions and the anisotropy effect of the uniaxial crystals. The evolution of the SDOC and SDOP for the radially polarized LGCSM beams is quite different from that of the radially polarized Gaussian-Schell-model beams. In addition, the propagation properties of the radially polarized LGCSM beams are closely related to the spatial coherence length, the mode order, and the ratio of extraordinary and ordinary reflective indices. The results show that the uniaxial crystals could modulate the evolution properties of the radially polarized LGCSM beams.

Focus shaping of partially coherent radially polarized vortex beam with tunable topological charge.

In this paper, we have introduced a new class of partially coherent vector vortex beams, named radially polarized multi-Gaussian Schell-model (MGSM) vortex beam, carrying the vortex phase with tunable topological charges (i.e., both integral and fractional values) as a natural extension of the radially polarized MGSM beam. The tight focusing properties of the radially polarized MGSM vortex beam passing through a high numerical aperture (NA) objective lens are investigated numerically based on the vectorial diffraction theory. Numerical results show that the focal intensity distributions of the radially polarized MGSM vortex beam can be shaped by regulating the structure of the correlation functions and the topological charge of vortex phase. In contrast with the integral vortex beam, the most intriguing property of the fractional vortex beam is that the focal intensity distribution at the focal plane can be nonuniformity and asymmetry, while such unique characteristics will vanish when the spatial coherence length is sufficiently small. Furthermore, some focal fields with novel structure, such as a focal spot with nonuniform asymmetric or an anomalous asymmetric hollow focal field, can be formed by choosing suitable fractional values of topological charge and spatial coherence length. Our results will be useful for optical trapping, especially for trapping of irregular particles or manipulation of absorbing particles.

Optimal Measurement Network of Pairwise Differences.

When both the difference between two quantities and their individual values can be measured or computationally predicted, multiple quantities can be determined from the measurements or predictions of select individual quantities and select pairwise differences. These measurements and predictions form a network connecting the quantities through their differences. Here, I analyze the optimization of such networks, where the trace (A-optimal), the largest eigenvalue (E-optimal), or the determinant (D-optimal) of the covariance matrix associated with the estimated quantities are minimized with respect to the allocation of the measurement (or computational) cost to different measurements (or predictions). My statistical analysis of the performance of such optimal measurement networks-based on large sets of simulated data-suggests that they substantially accelerate the determination of the quantities and that they may be useful in applications such as the computational prediction of binding free energies of candidate drug molecules.

Propagation properties of partially coherent crescent-like beams under maritime environment.

Based on the extended Huygens-Fresnel principle, the analytical expressions for the intensity distribution, effective radius of curvature, beam wander, Strehl ratio, and the power in the bucket of a partially coherent crescent-like (PCCL) beam under the maritime environment are derived. The propagation properties of the PCCL beams through the maritime environment are investigated in detail. Numerical results indicate that, for the maritime environment, the propagation properties and beam quality of a PCCL beam are closely related to its initial beam parameters and the turbulence parameters. Comparative analyses are performed for the new models under the marine turbulence and the terrestrial turbulence. It turns out that the marine turbulence influences the beam width and the beam wander more than the terrestrial turbulence does. Also, the beam quality of the PCCL beams in marine turbulence can be improved by choosing a large beam width, high coherence length, or short wavelength. The PCCL beams have a range-dependent tilt, which can be useful for some practical applications, such as traveling around an obstacle. The results are of significance for over-the-sea communication systems.

Molecular simulations minimally restrained by experimental data.

One popular approach to incorporating experimental data into molecular simulations is to restrain the ensemble average of observables to their experimental values. Here, I derive equations for the equilibrium distributions generated by restrained ensemble simulations and the corresponding expected values of observables. My results suggest a method to restrain simulations so that they generate distributions that are minimally perturbed from the unbiased distributions while reproducing the experimental values of the observables within their measurement uncertainties.

Optimization of the probability of orbital angular momentum for Laguerre-Gaussian beam in Kolmogorov and non-Kolmogorov turbulence.

We derive the probabilities of the signal OAM state and crosstalk OAM state for a Laguerre-Gaussian (LG) beam propagating through Kolmogorov and Non-Kolmogorov turbulence, and derive the accurate analytical function of the probability for the received OAM state modulated by an arbitrary receiver aperture. The probability of the detected OAM state with a receiver aperture for different values of the radius is demonstrated numerically. Our numerical results show that the probability of the signal OAM state remains almost invariant when the radius of the receiver aperture varies. The probability of the crosstalk OAM state decreases with the decrease of the radius of the receiver aperture, thus it can be optimized by choosing a suitable value of the radius of the receiver aperture. Our results will be useful in free-space optical communications.

Focus shaping of the radially polarized Laguerre-Gaussian-correlated Schell-model vortex beams.

In this paper, we introduce a new kind of partially coherent vector beam with special correlation function and vortex phase named radially polarized Laguerre-Gaussian-correlated Schell-model (LGCSM) vortex beam as a natural extension of scalar LGCSM vortex beam. The realizability conditions for such beam are derived. The tight focusing properties of a radially polarized LGCSM vortex beam passing through a high numerical aperture (NA) objective lens are investigated numerically based on the vectorial diffraction theory. We find that not only the transverse component but also the longitudinal component of the focal field distributions can be shaped by regulating the structures of the correlation functions, which is quite different from that of the conventional radially polarized partially coherent beam. Moreover, a series of wildly used focal field with novel structure, e.g., focal spot, flat-topped or doughnut beam profiles, needle-like focal field and controllable three-dimensional (3D) optical cage, were obtained. These results indicate that the focus shaping can be achieved by combining the regulation of the structures of the correlation functions with the regulation of beam parameters effectively. Our results may be useful for potential applications in optical trapping, optical high-resolution microscopy and optical data storage.

Evolution properties of the radially polarized multi-Gaussian Schell-model beam in uniaxial crystals.

The evolution properties of the normalized intensity distribution, the spectral degree of coherence (SDOC), and the spectral degree of polarization (SDOP) of the radially polarized multi-Gaussian Schell-model (MGSM) beam in uniaxial crystals are illustrated. Numerical results show that the intensity distribution of the radially polarized MGSM beam gradually evolves from a doughnut shape into an elliptical symmetric flattop shape and retains its elliptical flattop shape on further propagation in anisotropic crystals. The evolution behavior of the SDOC and SDOP for the radially polarized MGSM beam is quite different from that of the linearly polarized one. In addition, the influences of the spatial coherence length δ0, beam index M, and the ratio of the extraordinary refractive index to the ordinary refractive index ne/no of the uniaxial crystals on the evolution properties of the normalized intensity distribution, the SDOC, and the SDOP of the radially polarized MGSM beam are discussed in detail.

Serum vitamin D levels among children aged 0-12 years in the First Affiliated Hospital of Harbin Medical University, China.

Background: Vitamin D deficiency (VDD) and vitamin D insufficiency (VDI) are highly prevalent in the world, but the vitamin D status of children in northeast China is seldom investigated. The aim of this study was to clarify the prevalence of VDD and VDI among children in the First Affiliated Hospital of Harbin Medical University in Heilongjiang province in China. Methods: We collected data from 9795 children who were outpatients aged 0-12 years who visited the First Affiliated Hospital of Harbin Medical University from September 2014 to August 2016. Serum 25-hydroxy vitamin D [25(OH)D] levels were determined by chemiluminescent immunoassay and categorized as <20, 20-30 and >30 ng/mL. Results: The highest mean level of serum 25(OH)D was found at the 1-3 years stage (31.14 ng/mL) and the lowest at 6-12 years stage (18.58 ng/mL). The mean serum 25(OH)D level among school girls (17.86 ng/mL) was lower than that of boys (19.12 ng/mL). The prevalence of vitamin D sufficiency during 2014 was only 17.2%, but increased to ~45% in 2016. Conclusions: The prevalence of VDD and insufficiency among children in the First Affiliated Hospital of Harbin Medical University is high, especially among children aged 6-12 years.

Position 22 of the V3 loop is associated with HIV infectivity.

Human immunodeficiency virus subtype 1B (HIV-1B) binds to the CD4 receptor and co-receptor CCR5 or CXCR4 to enter T lymphocytes. The amino acid sequence of the HIV envelope glycoprotein V3 region determines the co-receptor tropism, thereby influencing the infectivity of the virus. Our research group previously found that the amino acid at position 22 of the V3 region may affect the infectivity of the virus, and in this study, we tested this hypothesis. We constructed pseudoviruses by changing the amino acids at position 22 of the V3 region in CCR5-tropic and CXCR4-tropic viruses and tested their infectivity. When the amino acid at V3 position 22 was altered in the CCR5- and CXCR4-tropic viruses, their ability to infect cells decreased to 20.6% and 17.14%, respectively. Therefore, we propose that residue 22 in the V3 region of subtype HIV-1B significantly influences the infectivity of the virus.