Designing Stable Bimetallic Nanoclusters via an Iterative Two-Step Optimization Approach

Determining the energetically most favorable structure of nanoparticles is a fundamentally important task towards understanding their stability. In the case of bimetallic nanoclusters, their vast configurational space makes it especially...

What Is the Temperature? Modern Outlook on the Concept of Temperature

The meaning and evolution of the notion of “temperature” (which is a key concept for the condensed and gaseous matter theories) is addressed from the different points of view. The concept of temperature turns out to be much more fundamental than it is conventionally thought. In particular, the temperature may be introduced for the systems built of “small” number of particles and particles in rest. The Kelvin temperature scale may be introduced into the quantum and relativistic physics due to the fact, that the efficiency of the quantum and relativistic Carnot cycles coincides with that of the classical one. The relation of the temperature to the metrics of the configurational space describing the behavior of system built from non-interacting particles is demonstrated. The Landauer principle asserts that the temperature of the system is the only physical value defining the energy cost of isothermal erasing of the single bit of information. The role of the temperature the cosmic microwave background in the modern cosmology is discussed.

A Minimal, Adaptive Binning Scheme for Weighted Ensemble Simulations

A promising approach for simulating rare events with rigorous kinetics is the weighted ensemble path sampling strategy. One challenge of this strategy is the division of configurational space into bins for sampling. Here we present a minimal adaptive binning (MAB) scheme for the automated, adaptive placement of bins along a progress coordinate within the framework of the weighted ensemble strategy. Results reveal that the MAB binning scheme, despite its simplicity, is more efficient than a manual, fixed binning scheme in generating transitions over large free energy barriers, generating a diversity of pathways, estimating rate constants, and sampling conformations. The scheme is general and extensible to any rare-events sampling strategy that employs progress coordinates.

SAMPL7 TrimerTrip Host-Guest Binding Affinities from Extensive Alchemical and End-Point Free Energy Calculations

<p></p><p> The prediction of host-guest binding affinities with computational modelling is still a challenging task. In the 7^th statistical assessment of the modeling of proteins and ligands (SAMPL) challenge, a new host named TrimerTrip was synthesized and the thermodynamic parameters of 16 structurally diverse guests binding to the host were characterized. In the TrimerTrip-guest challenge, only structures of the host and the guests are provided, which indicates that the predictions of both the binding poses and the binding affinities are under assessment. In this work, starting from the binding poses obtained from our previous enhanced sampling simulations in the configurational space, we perform extensive alchemical and end-point free energy calculations to calculate the host-guest binding affinities retrospectively. The alchemical predictions with two widely accepted charge schemes (i.e. AM1-BCC and RESP) are in good agreement with the experimental reference, while the end-point estimates perform poorly in reproducing the experimental binding affinities. Aside from the absolute value of the binding affinity, the rank of binding free energies is also crucial in drug design. Surprisingly, the end-point MM/PBSA method seems very powerful in reproducing the experimental rank of binding affinities. Although the length of our simulations is long and the intermediate spacing is dense, the convergence behavior is not very good, which may arise from the flexibility of the host molecule. Enhanced sampling techniques in the configurational space may be required to obtain fully converged sampling. Further, as the length of sampling in alchemical free energy calculations already achieves several hundred ns, performing direct simulations of the binding/unbinding event in the physical space could be more useful and insightful. More details about the binding pathway and mechanism could be obtained in this way. The nonequilibrium method could also be a nice choice if one insists to use the alchemical method, as the intermediate sampling is avoided to some extent. </p><p></p>

SAMPL7 TrimerTrip Host-Guest Binding Affinities from Extensive Alchemical and End-Point Free Energy Calculations

<p></p><p> The prediction of host-guest binding affinities with computational modelling is still a challenging task. In the 7^th statistical assessment of the modeling of proteins and ligands (SAMPL) challenge, a new host named TrimerTrip was synthesized and the thermodynamic parameters of 16 structurally diverse guests binding to the host were characterized. In the TrimerTrip-guest challenge, only structures of the host and the guests are provided, which indicates that the predictions of both the binding poses and the binding affinities are under assessment. In this work, starting from the binding poses obtained from our previous enhanced sampling simulations in the configurational space, we perform extensive alchemical and end-point free energy calculations to calculate the host-guest binding affinities retrospectively. The alchemical predictions with two widely accepted charge schemes (i.e. AM1-BCC and RESP) are in good agreement with the experimental reference, while the end-point estimates perform poorly in reproducing the experimental binding affinities. Aside from the absolute value of the binding affinity, the rank of binding free energies is also crucial in drug design. Surprisingly, the end-point MM/PBSA method seems very powerful in reproducing the experimental rank of binding affinities. Although the length of our simulations is long and the intermediate spacing is dense, the convergence behavior is not very good, which may arise from the flexibility of the host molecule. Enhanced sampling techniques in the configurational space may be required to obtain fully converged sampling. Further, as the length of sampling in alchemical free energy calculations already achieves several hundred ns, performing direct simulations of the binding/unbinding event in the physical space could be more useful and insightful. More details about the binding pathway and mechanism could be obtained in this way. The nonequilibrium method could also be a nice choice if one insists to use the alchemical method, as the intermediate sampling is avoided to some extent. </p><p></p>

SAMPL7 TrimerTrip Host-Guest Binding Affinities from Extensive Alchemical and End-Point Free Energy Calculations

<p>The prediction of host-guest binding affinities with computational modelling is still a challenging task. In the 7^th statistical assessment of the modeling of proteins and ligands (SAMPL) challenge, a new host named TrimerTrip is synthesized and the thermodynamic parameters of 16 structurally diverse guests binding to the host are characterized. The challenge provides only structures of the host and the guests, which indicates that the predictions of both the binding poses and the binding affinities are under assessment. In this work, starting from the binding poses obtained from our previous enhanced sampling simulations in the configurational space, we perform extensive alchemical and end-point free energy calculations to calculate the host-guest binding affinities. The alchemical predictions with two widely accepted charge schemes (i.e. AM1-BCC and RESP) are in good agreement with the experimental reference, while the end-point estimates show significant deviations. Surprisingly, the end-point MM/PBSA method seems very powerful in reproducing the experimental rank of binding affinities. Although the length of our simulations is already very long and the intermediate spacing is very dense, the convergence behavior is not very good, which may arise from the flexibility of the host molecule. Enhanced sampling techniques in the configurational space may be required to obtain fully converged sampling. Further, as the length of sampling in alchemical free energy calculations already achieves several hundred ns, performing direct simulations of the binding/unbinding event in the physical space could be more useful and insightful. More details about the binding pathway and mechanism could be obtained in this way. </p>

BAR-based Optimum Adaptive Steered MD for Configurational Sampling

<p>Previously we proposed the equilibrium and nonequilibrium adaptive alchemical free energy simulation methods Optimum Bennett’s Acceptance Ratio (OBAR) and Optimum Crooks’ Equation (OCE). They are based on the statistically optimal bidirectional reweighting estimator named Bennett’s Acceptance Ratio (BAR) or Crooks’ Equation (CE). They perform initial sampling in the staging alchemical transformation and then determine the importance rank of different states via the time-derivative of the variance (TDV). The method is proven to give speedups compared with the equal time rule. In the current work, we extended the time derivative of variance guided adaptive sampling method to the configurational space, falling in the term of Steered MD (SMD). The SMD approach biasing physically meaningful collective variable (CV) such as one dihedral or one distance to pulling the system from one conformational state to another. By minimizing the variance of the free energy differences along the pathway in an optimized way, a new type of adaptive SMD (ASMD) is introduced. As exhibits in the alchemical case, this adaptive sampling method outperforms the traditional equal-time SMD in nonequilibrium stratification. Also, the method gives much more efficient calculation of potential of mean force than the selection criterion based ASMD scheme, which is proven to be more efficient than traditional SMD. The variance-linearly-dependent minus time derivative of overall variance proposed for OBAR and OCE criterion is extended to determine the importance rank of the nonequilibrium pulling in the configurational space. It is shown that the importance rank given by the standard deviation of the free energy difference is wrong, but by correcting it with the simulation time we obtain the true importance rank in nonequilibrium stratification. The OCE workflow is periodicity-of-CV dependent while ASMD is not. In the non-periodic CV case, the end-state discrimination in the SD rank is eliminated in the TDV rank, while in the periodic CV case the correction introduced in the TDV rank is not that significant. The performance is demonstrated in a dihedral flipping case and two distance pulling cases, accounting for periodic and non-periodic CVs, respectively. </p>