113 research outputs found
Towards Automated Benchmarking of Atomistic Forcefields: Neat Liquid Densities and Static Dielectric Constants from the ThermoML Data Archive
Atomistic molecular simulations are a powerful way to make quantitative
predictions, but the accuracy of these predictions depends entirely on the
quality of the forcefield employed. While experimental measurements of
fundamental physical properties offer a straightforward approach for evaluating
forcefield quality, the bulk of this information has been tied up in formats
that are not machine-readable. Compiling benchmark datasets of physical
properties from non-machine-readable sources require substantial human effort
and is prone to accumulation of human errors, hindering the development of
reproducible benchmarks of forcefield accuracy. Here, we examine the
feasibility of benchmarking atomistic forcefields against the NIST ThermoML
data archive of physicochemical measurements, which aggregates thousands of
experimental measurements in a portable, machine-readable, self-annotating
format. As a proof of concept, we present a detailed benchmark of the
generalized Amber small molecule forcefield (GAFF) using the AM1-BCC charge
model against measurements (specifically bulk liquid densities and static
dielectric constants at ambient pressure) automatically extracted from the
archive, and discuss the extent of available data. The results of this
benchmark highlight a general problem with fixed-charge forcefields in the
representation low dielectric environments such as those seen in binding
cavities or biological membranes
Quantifying configuration-sampling error in Langevin simulations of complex molecular systems
While Langevin integrators are popular in the study of equilibrium properties of complex systems, it is challenging to estimate the timestep-induced discretization error: the degree to which the sampled phase-space or configuration-space probability density departs from the desired target density due to the use of a finite integration timestep. Sivak et al., introduced a convenient approach to approximating a natural measure of error between the sampled density and the target equilibrium density, the Kullback-Leibler (KL) divergence, in phase space, but did not specifically address the issue of configuration-space properties, which are much more commonly of interest in molecular simulations. Here, we introduce a variant of this near-equilibrium estimator capable of measuring the error in the configuration-space marginal density, validating it against a complex but exact nested Monte Carlo estimator to show that it reproduces the KL divergence with high fidelity. To illustrate its utility, we employ this new near-equilibrium estimator to assess a claim that a recently proposed Langevin integrator introduces extremely small configuration-space density errors up to the stability limit at no extra computational expense. Finally, we show how this approach to quantifying sampling bias can be applied to a wide variety of stochastic integrators by following a straightforward procedure to compute the appropriate shadow work, and describe how it can be extended to quantify the error in arbitrary marginal or conditional distributions of interest
The Selectivity and Functional Connectivity of the Anterior Temporal Lobes
One influential account asserts that the anterior temporal lobe (ATL) is a domain-general hub for semantic memory. Other evidence indicates it is part of a domain-specific social cognition system. Arbitrating these accounts using functional magnetic resonance imaging has previously been difficult because of magnetic susceptibility artifacts in the region. The present study used parameters optimized for imaging the ATL, and had subjects encode facts about unfamiliar people, buildings, and hammers. Using both conjunction and region of interest analyses, person-selective responses were observed in both the left and right ATL. Neither building-selective, hammer-selective nor domain-general responses were observed in the ATLs, although they were observed in other brain regions. These findings were supported by “resting-state” functional connectivity analyses using independent datasets from the same subjects. Person-selective ATL clusters were functionally connected with the brain's wider social cognition network. Rather than serving as a domain-general semantic hub, the ATLs work in unison with the social cognition system to support learning facts about others
The dynamic conformational landscape of the protein methyltransferase SETD8
Elucidating the conformational heterogeneity of proteins is essential for understanding
protein function and developing exogenous ligands. With the rapid development of experimental
and computational methods, it is of great interest to integrate these approaches to illuminate the
conformational landscapes of target proteins. SETD8 is a protein lysine methyltransferase (PKMT),
which functions in vivo via the methylation of histone and nonhistone targets. Utilizing covalent
inhibitors and depleting native ligands to trap hidden conformational states, we obtained diverse
X-ray structures of SETD8. These structures were used to seed distributed atomistic molecular
dynamics simulations that generated a total of six milliseconds of trajectory data. Markov state
models, built via an automated machine learning approach and corroborated experimentally, reveal
how slow conformational motions and conformational states are relevant to catalysis. These
findings provide molecular insight on enzymatic catalysis and allosteric mechanisms of a PKMT via
its detailed conformational landscape
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