Davide Branduardi

Davide Branduardi
Crucell · Crucell Vaccine Institute

PhD in Chemistry at ETH Zurich

About

43
Publications
6,701
Reads
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5,119
Citations
Citations since 2017
1 Research Item
3481 Citations
20172018201920202021202220230200400600
20172018201920202021202220230200400600
20172018201920202021202220230200400600
20172018201920202021202220230200400600
Introduction
My main research focus in is computational characterization of free energy differences of conformational changes and catalytic mechanism in biomolecules. I apply and develop new methodologies that mainly exploit molecular dynamics and simulations in general.
Additional affiliations
May 2011 - September 2013
Max Planck Institute of Biophysics
Position
  • PostDoc Position
March 2009 - May 2011
Istituto Italiano di Tecnologia
Position
  • PostDoc Position
February 2004 - February 2009
ETH Zurich
Position
  • PhD

Publications

Publications (43)
Article
The PLUMED consortium unifies developers and contributors to PLUMED, an open-source library for enhanced- sampling, free-energy calculations and the analysis of molecular dynamics simulations. Here, we outline our efforts to promote transparency and reproducibility by disseminating protocols for enhanced-sampling molecular simulations.
Chapter
This chapter focuses on metadynamics, which was first introduced in 2002 and then improved with several variants in the past decade. It provides an introduction to the basic concepts of molecular dynamics and of free-energy calculations. When appropriate collective variables (CVs) are used, the free-energy landscape provides a quantitative picture...
Article
Enhancing sampling and analyzing simulations are central issues in molecular simulation. Recently, we introduced PLUMED, an open-source plug-in that provides some of the most popular molecular dynamics (MD) codes with implementations of a variety of different enhanced sampling algorithms and collective variables (CVs). The rapid changes in this fie...
Article
Acid ceramidase (AC) is an intracellular cysteine amidase that catalyzes the hydrolysis of the lipid messenger ceramide. By regulating ceramide levels in cells, AC may contribute to the regulation of cancer cell proliferation and senescence and to the response to cancer therapy. We recently identified the antitumoral agent carmofur (4a) as the firs...
Article
We used density functional theory to investigate the capacity for carbon monoxide (CO) release of five newly synthesized manganese-containing CO-releasing molecules (CO-RMs), namely CORM-368 (1), CORM-401 (2), CORM-371 (3), CORM-409 (4), and CORM-313 (5). The results correctly discriminated good CO releasers (1 and 2) from a compound unable to rele...
Article
Metadynamics is an established sampling method aimed at reconstructing the free-energy surface relative to a set of appropriately chosen collective variables. In standard metadynamics the free-energy surface is filled by the addition of Gaussian potentials of pre-assigned and typically diagonal covariance. Asymptotically the free-energy surface is...
Article
Full-text available
The N-terminal nucleophile (Ntn) hydrolases are a superfamily of enzymes specialized in the hydrolytic cleavage of amide bonds. Even though several members of this family are emerging as innovative drug targets for cancer, inflammation, and pain, the processes through which they catalyze amide hydrolysis remains poorly understood. In particular, th...
Data
Projection of the gradients of S. Absolute value of the projection of the gradients of S over the gradient of relevant interatomic distances (see Text S3 for details). High values denote interatomic distances which play a pivotal role determining the mean force along the reaction progress. (TIF)
Data
Superposition of the transition state (TS) structures for the reaction in CBAH solution and in CBAH. TS structures were identified along steered-MD/PCVs simulations. The TS geometry for the reaction in aqueous solution is reported with white carbon, while the TS geometry for the enzyme catalyzed reaction is reported with black carbons. (TIF)
Data
Comparison between TAU hydrolysis in CBAH and in solution. Activation barriers for the first step of TAU hydrolysis catalyzed by CBAH (line) and in aqueous solution (dashed line), estimated from work profiles obtained from steered-MD/PCVs simulations. In the lower panel, relevant distances are plotted as a function of S (progress along the path). (...
Data
PROPKA contributions to the final pKa for Cys2 thiol group. (DOC)
Data
Convergence of free energy obtained from US/PCVs simulations. (DOC)
Data
Effect of pH on CBAH activity. The figure is adapted from Gopal-Srivastava R, Hylemon PB (1988) Purification and characterization of bile salt hydrolase from Clostridium perfringens. J Lipid Res 29: 1079–1085. (TIF)
Data
pKa prediction of titrable sites in CBAH by PROPKA. (DOC)
Data
Zero point charge mutants of CBAH. (DOC)
Data
Work profile of the first step of TAU hydrolysis by CBAH over S. Work profile of the first step of TAU hydrolysis by CBAH over S by steered-MD, compared with free energy profile obtained with umbrella sampling (and also reported in Figure 6A of the main text). (TIF)
Data
Reactant complex formed by Cys-OMe and TAU substrate. Reactant complex formed by Cys-OMe and TAU substrate as a model system to simulate amide hydrolysis in solution. Water molecules within 6 Å from the reactive center are displayed. (TIF)
Data
First step of TAU hydrolysis by Cys-OMe in solution. A, B, and C are key steps for the cleavage of TAU amide bond. (TIF)
Data
Free energy for TAU hydrolysis in CBAH by steered-MD/PCVs. (DOC)
Data
Free energy for TAU hydrolysis in solution by steered-MD/PCVs. (DOC)
Article
A homeostatic concentration of glutamate in the synaptic cleft ensures a correct signal transduction along the neuronal network. An unbalance in this concentration can lead to neuronal death and to severe neurodegenerative diseases such as Alzheimer's or Parkinson's. Glutamate transporters play a crucial role in this respect because they are respon...
Article
Full-text available
Computational studies of ligand-protein binding are crucial for properly designing novel compounds of potential pharmacological interest. In this respect, researchers are increasingly interested in steered molecular dynamics for ligand-protein binding and unbinding studies. In particular, it has been suggested that analyzing the work profiles along...
Article
In this work, we exploit the chirality index introduced in (Pietropaolo et al., Proteins 2008, 70, 667) as an effective descriptor of the secondary structure of proteins to explore their complex free-energy landscape. We use the chirality index as an alternative metrics in the path collective variables (PCVs) framework and we show in the prototypic...
Article
Recently, covalent drugs have attracted great interest in the drug discovery community, with successful examples that have demonstrated their therapeutic effects. Here, we focus on the covalent inhibition of the fatty acid amide hydrolase (FAAH), which is a promising strategy in the treatment of pain and inflammation. Among the most recent and pote...
Article
Herein, we propose a conceptually innovative approach to investigating reaction mechanisms. This study demonstrates the importance of considering explicitly the effects of large amplitude motions, aside from the intrinsic reaction coordinate, when tuning the free energy landscape of reaction pathways. We couple the path collective variables method...
Article
Free-energy pathway methods show great promise in computing the mode of action and the free energy profile associated with the binding of small molecules with proteins, but are generally very computationally demanding. Here we apply a novel approach based on metadynamics and path collective variables. We show that this combination is able to find a...
Article
Here we present a program aimed at free-energy calculations in molecular systems. It consists of a series of routines that can be interfaced with the most popular classical molecular dynamics (MD) codes through a simple patching procedure. This leaves the possibility for the user to exploit many different MD engines depending on the system simulate...
Article
The cis-trans isomerization of N-methylacetamide (NMA), a model peptidic fragment, is studied theoretically in vacuo and in explicit water solvent at 300 K using the metadynamics technique. The computed cis-trans free energy difference is very similar for NMA(g) and NMA(aq), in agreement with experimental measurements of population ratios and theor...
Article
Full-text available
The influence of the state of the bound nucleotide (ATP, ADP-Pi, or ADP) on the conformational free-energy landscape of actin is investigated. Nucleotide-dependent folding of the DNase-I binding (DB) loop in monomeric actin and the actin trimer is carried out using all-atom molecular dynamics (MD) calculations accelerated with a multiscale implemen...
Article
Full-text available
Although studies of cell cycle perturbation and growth inhibition are common practice, they are unable to properly measure the activity of cell cycle checkpoints and frequently convey misinterpretation or incomplete pictures of the response to anticancer treatment. A measure of the strength of the treatment response of all checkpoints, with their t...
Article
Two of the main challenges of modern molecular biology are the determination of the biologically active conformation of a protein from the information encoded in its amino acid sequence and the understanding of the series of events that brings this sequence to the native state. However, for a complete comprehension of the folding process, it's of f...
Article
Kinase large-scale conformational rearrangement is an issue of enormous biological and pharmacological relevance. Atomistic simulations able to capture the dynamics and the energetics of kinase large-scale motions are still in their infancy. Here, we present a computational study in which the atomistic dynamics of the "open-to-closed" movement of t...
Conference Paper
The polymerization of actin monomers into filaments and larger structures, e.g., bundles, is a key process in the machinery of the cell. In the last decade, experimental measurements of actin and actin-related proteins have greatly increased our understanding of both the mechanism of cell motility and the role of cellular components that regulate f...
Article
In this work, we shed new light on a much-studied case of beta-hairpin folding by means of advanced molecular dynamics simulations. A fully atomistic description of the protein and the solvent molecule is used, together with metadynamics, to accelerate the sampling and estimate free-energy landscapes. This is achieved using the path collective vari...
Article
The translocation of ions and water across cell membranes is a prerequisite for many of life's processes. K(+) channels are a diverse family of integral membrane proteins through which K(+) can pass selectively. There is an ongoing debate about the nature of conformational changes associated with the opening and closing and conductive and nonconduc...
Article
Full-text available
The authors present a new method for searching low free energy paths in complex molecular systems at finite temperature. They introduce two variables that are able to describe the position of a point in configurational space relative to a preassigned path. With the help of these two variables the authors combine features of approaches such as metad...
Article
Alkali cations can affect the catalytic efficiency of enzymes. This is particularly true when dealing with enzymes whose substrate bears a formal positive charge. Computational and biochemical approaches have been combined to shed light on the atomic aspects of the role of Li(+), Na(+), and K(+) on human acetylcholinesterase (hAChE) ligand binding....
Chapter
Cyclin-dependent kinases (CDKs) are mostly known for their role in the cell cycle regulation. The activation mechanism of all CDKs involves the association with a regulatory protein, generally a cyclin, that binds to the kinase unit and stabilizes a catalytically active conformation. Active and inactive conformations of CDKs are characterized by th...
Article
Binding sites for SiH2 on Si(001) are investigated theoretically by using several different methods. Possible local minima are first sampled by classical molecular dynamics simulations of the SiH2/Si(001) impact, allowing for a preliminary, fast selection. A further refinement is carried out by geometry optimizations using semiempirical tight-bindi...
Article
We study the ligand (tetramethylammonium) recognition by the peripheral anionic site and its penetration of the human AChE gorge by using atomistic molecular dynamics simulations and our recently developed metadynamics method. The role of both the peripheral anionic site and the formation of cation-pi interactions in the ligand entrance are clearly...
Article
Full-text available
Topotecan (TPT) is a topoisomerase I inhibitor, and like the other drugs of this family, it is believed to act in a specific way on cells in S phase at the time of treatment. Exploiting a new method, coupling a particular experimental plan with computer simulation, a complete quantitative study of the time dependence and dose dependence of the acti...

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