1,726 research outputs found
Water regulates the residence time of Benzamidine in Trypsin
We simulate with state-of-the-art enhanced sampling techniques the binding of
Benzamidine to Trypsin which is a much studied and paradigmatic ligand-protein
system. We use machine learning methods and in particular Time-lagged
Independent Component Analysis to determine efficient collective coordinates.
These coordinates are used to perform On-the-fly Probability Enhanced Sampling
simulations, which we adapt to calculate also the ligand residence time. Our
results, both static and dynamic, are in good agreement with experiments. We
underline the role of water in the unbinding process and find that the presence
of a water molecule located at the bottom of the binding pocket allows via a
network of hydrogen bonds the ligand to be released into the solution. On a
finer scale, even when unbinding is allowed, another water molecule further
modulates the exit time
Inelastic electron injection in a water chain
Irradiation of biological matter triggers a cascade of secondary particles
that interact with their surroundings, resulting in damage. Low-energy
electrons are one of the main secondary species and electron-phonon interaction
plays a fundamental role in their dynamics. We have developed a method to
capture the electron-phonon inelastic energy exchange in real time and have
used it to inject electrons into a simple system that models a biological
environment, a water chain. We simulated both an incoming electron pulse and a
steady stream of electrons and found that electrons with energies just outside
bands of excited molecular states can enter the chain through phonon emission
or absorption. Furthermore, this phonon-assisted dynamical behaviour shows
great sensitivity to the vibrational temperature, highlighting a crucial
controlling factor for the injection and propagation of electrons in water
The role of water in host-guest interaction
One of the main applications of atomistic computer simulations is the
calculation of ligand binding energies. The accuracy of these calculations
depends on the force field quality and on the thoroughness of configuration
sampling. Sampling is an obstacle in modern simulations due to the frequent
appearance of kinetic bottlenecks in the free energy landscape. Very often this
difficulty is circumvented by enhanced sampling techniques. Typically, these
techniques depend on the introduction of appropriate collective variables that
are meant to capture the system's degrees of freedom. In ligand binding, water
has long been known to play a key role, but its complex behaviour has proven
difficult to fully capture. In this paper we combine machine learning with
physical intuition to build a non-local and highly efficient water-describing
collective variable. We use it to study a set of of host-guest systems from the
SAMPL5 challenge. We obtain highly accurate binding energies and good agreement
with experiments. The role of water during the binding process is then analysed
in some detail
OneOPES, a Combined Enhanced Sampling Method to Rule Them All
Enhanced sampling techniques have revolutionized molecular dynamics (MD) simulations, enabling the study of rare events and the calculation of free energy differences in complex systems. One of the main families of enhanced sampling techniques uses physical degrees of freedom called collective variables (CVs) to accelerate a system’s dynamics and recover the original system’s statistics. However, encoding all the relevant degrees of freedom in a limited number of CVs is challenging, particularly in large biophysical systems. Another category of techniques, such as parallel tempering, simulates multiple replicas of the system in parallel, without requiring CVs. However, these methods may explore less relevant high-energy portions of the phase space and become computationally expensive for large systems. To overcome the limitations of both approaches, we propose a replica exchange method called OneOPES that combines the power of multireplica simulations and CV-based enhanced sampling. This method efficiently accelerates the phase space sampling without the need for ideal CVs, extensive parameters fine tuning nor the use of a large number of replicas, as demonstrated by its successful applications to protein–ligand binding and protein folding benchmark systems. Our approach shows promise as a new direction in the development of enhanced sampling techniques for molecular dynamics simulations, providing an efficient and robust framework for the study of complex and unexplored problems
Rare Event Kinetics from Adaptive Bias Enhanced Sampling
We introduce a novel enhanced sampling approach named OPES flooding for
calculating the kinetics of rare events from atomistic molecular dynamics
simulation. This method is derived from the
On-the-fly-Probability-Enhanced-Sampling (OPES) approach [Invernizzi and
Parrinello, JPC Lett. 2020], which has been recently developed for calculating
converged free energy surfaces for complex systems. In this paper, we describe
the theoretical details of the OPES flooding technique and demonstrate the
application on three systems of increasing complexity: barrier crossing in a
two-dimensional double well potential, conformational transition in the alanine
dipeptide in gas phase, and the folding and unfolding of the chignolin
polypeptide in aqueous environment. From extensive tests, we show that the
calculation of accurate kinetics not only requires the transition state to be
bias-free, but the amount of bias deposited should also not exceed the
effective barrier height measured along the chosen collective variables. In
this vein, the possibility of computing rates from biasing suboptimal order
parameters has also been explored. Furthermore, we describe the choice of
optimum parameter combinations for obtaining accurate results from limited
computational effort
Educational pathway of people with Spinal Cord Injuries: a participatory research project starting from the illness narratives
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