Leandro Martínez

• Dr.
• Professor (Associate) at State University of Campinas (UNICAMP)

The analysis of structural mobility in molecular dynamics plays a key role in data interpretation, particularly in the simulation of biomolecules. The most common mobility measures computed from simulations are the Root Mean Square Deviation (RMSD) and Root Mean Square Fluctuations (RMSF) of the structures. These are computed after the alignment of...

Nuclear hormone receptors (NRs) are major targets for pharmaceutical development. Many experiments demonstrate that their C-terminal Helix (H12) is more flexible in the ligand-binding domains (LBDs) without ligand, this increased mobility being correlated with transcription repression and human diseases. Crystal structures have been obtained in whi...

Large-scale electronic structure calculations usually involve huge nonlinear eigenvalue problems. A method for solving these problems without employing expensive eigenvalue decompositions of the Fock matrix is presented in this work. The sparsity of the input and output matrices is preserved at every iteration, and the memory required by the algori...

Adequate initial configurations for molecular dynamics simulations consist of arrangements of molecules distributed in space in such a way to approximately represent the system's overall structure. In order that the simulations are not disrupted by large van der Waals repulsive interactions, atoms from different molecules must keep safe pairwise di...

Thyroid hormone receptors (TR) are hormone-dependent transcription regulators that play a major role in human health, development, and metabolic functions. The thyroid hormone resistance syndrome, diabetes, obesity, and some types of cancer are just a few examples of important diseases that are related to TR malfunctioning, particularly impaired ho...

This study investigates the utilization of squid pen waste through a biocompatible ionic liquid approach, focusing on choline acetate, [Ch][OAc]. This ionic liquid effectively extracts over 80 wt % of protein from squid pen waste. To optimize the extraction process, a factorial design of experiments was employed to achieve a protein recovery of 75%...

The molecular mechanisms by which osmolytes promote protein denaturation or protection are under permanent debate, because the characterization of the structure and solvation of denatured states is a major challenge. Here we show that similar qualitative interactions occur between urea and TMAO and the β-sheet SH3 domain and the helical B domain of...

This study examines the influence of cation hydrophobicity on protein solvation in aqueous solutions of Ionic Liquids. Ubiquitin solvation structures and thermodynamics in systems with 1-ethyl-3-methylimidazolium ([EMIM]⁺) and 1-butyl-3-methylimidazolium ([BMIM]⁺) are studied using molecular dynamics simulations, Minimum-Distance distribution funct...

Accurately predicting the diverse bound-state conformations of small molecules is crucial for successful drug discovery and design, particularly when detailed protein-ligand interactions are unknown. Established tools exist, but efficiently exploring the vast conformational space remains challenging. This work introduces Moltiverse, a novel protoco...

In this work, the foundation of a biobased ionic liquid utilization of squid waste has been scrutinized. An ionic liquid screening showed that the biocompatible ionic liquid choline acetate, [Ch][OAc], can extract more than 80 wt% of the protein and precipitate it upon solvent swing between ethanol and water. Process parameter optimization was carr...

Accurately predicting the diverse bound-state conformations of small molecules is crucial for successful drug discovery, particularly when detailed protein-ligand interactions are unknown. Established tools exist, but exploring the vast conformational space efficiently remains a challenge. This work introduces Moltiverse, a novel protocol using enh...

Plasmodium falciparum apical membrane antigen 1 (PfAMA1) is a surface protein found in two stages of the malaria life cycle. This is a protein involved in a reorientation movement of the parasite so that cell invasion occurs in the so-called “moving junction”, relevant when the membranes of the parasite and the host are in contact. The structure of...

The present study utilizes molecular dynamics simulations to examine how different anions compete for protein solvation in aqueous solutions of ionic liquids (ILs). Ubiquitin is used as model protein and studied in IL mixtures sharing the same cation, 1-ethyl-3-methylimidazolium (EMIM), and two different anions in the same solution, from combinatio...

The proteome of Plasmodium falciparum (Pf) is abundant in intrinsically disordered proteins (IDPs). Their important roles in the malaria life cycle and the limitations of experimental and computational methods to study this class of proteins hinder the development of antimalarial drugs. At the same time, the growing interest in IDPs and theoretical...

2,2,2-Trifluoroethanol (TFE) is a well-known protein α-helix stabilizer; nevertheless, after much investigation, no consensus has been reached on TFE's stabilizing mechanism. TFE alters the structure of water and affects its dielectric properties, but also competes with it for hydrogen bonds with the backbone and side chains of proteins. Thus, indi...

Ionic liquids (ILs) are utilized as enzymatic reaction solvents and as protein structure protectants or denaturants in biotechnological applications. They can develop a wide spectrum of interactions with macromolecules due to their chemical complexity. Understanding how ILs interact with protein conformations is crucial to fine-tuning their action....

N-body simulations and trajectory analysis rely on the calculation of attributes that depend on pairwise particle distances within a cutoff. Interparticle potential energies, forces, distribution functions, neighbor lists, and distance-dependent distributions, for example, must be calculated. Cell lists are widely used to avoid computing distances...

Computer Physics Communications Available online 16 June 2022, 108452 In Press, Journal Pre-proofWhat are Journal Pre-proof articles? CellListMap.jl: Efficient and customizable cell list implementation for calculation of pairwise particle properties within a cutoff Author links open overlay panelLeandroMartínez https://doi.org/10.1016/j.cpc.2022.10...

Distribution functions are used to investigate the interactions between the components of condensed-phase systems, while allowing the computation of thermodynamic properties that can be probed experimentally. Radial distribution functions are the most fundamental and easily understood of these distributions, but fail to provide a molecular picture...

Motivation: Protein structure modeling can be improved by the use of distance constraints between amino acid residues, provided such data reflects-at least partially-the native tertiary structure of the target system. In fact, only a small subset of the native contact map is necessary to successfully drive the model conformational search, so one i...

Simulating huge biomolecular complexes of million atoms at relevant biological time scales is becoming accessible to the broad scientific community. That proves to be crucial for urgent responses against emergent diseases in real time. Yet, there are still issues to sort regarding the system setup so that molecular dynamics (MD) simulations can be...

A computação em nuvem tem se tornado cada vez mais frequente em empresas e universidades, principalmente devido ao fato da nuvem computacional ser mais facilmente administrada uma vez que seu ambiente esteja devidamente configurado. Entretanto, há resistência na implantação de ambientes de computação de alto desempenho em nuvem e isso, provavelment...

Ionic liquids are versatile solvents that have been used in various applications: as green solvents, catalysts, and in biotechnological systems. The optimization of ionic liquids use can be achieved by an understanding of its behavior in chemical systems. Here, the interaction between EMIMDCA and four different folding states of the ubiquitin is st...

Simulating huge biomolecular complexes of million atoms at relevant biological timescales is becoming accessible to the broad scientific community. That proves to be crucial for urgent responses against emergent diseases in real time. Yet, there are still some issues to be overcome regarding the system setup so that Molecular Dynamics (MD) simulati...

Ionic liquids are versatile compounds for biotechnological applications. However, even the chemical systems composed only of the IL, water, and of the biomolecules display complex interactions that are not reducible in terms of the possible pairs of components. Here, we illustrate this complexity and provide a molecular understanding of cooperative...

Simulações de dinâmica clássica são ferramentas úteis para estudar fenômenos com bases mecânicas bem estabelecidas, tendo como únicos pré-requisitos o entendimento das soluções físicas do sistema e a descrição clara dessas soluções e seus passos para um computador por meio de uma linguagem de programação. Neste trabalho, aprendemos e exploramos uma...

Two-pore domain potassium (K2P) channels maintain the cell’s background conductance by stabilizing the resting membrane potential. They assemble as dimers possessing four transmembrane helices in each subunit. K2P channels were crystallized in “up” and “down” states. The movements of the pore-lining transmembrane TM4 helix produce the aperture or c...

Surface-specific spectroscopic data has shown that urea undergoes a shift in orientation at protein surfaces in acidic media. Since urea denatures proteins at a wide range of pHs, the variable chemical nature of protein-urea interactions has been used to support an indirect mechanism of urea-induced denaturation. Here, we use molecular dynamics sim...

The analysis of amino acid coevolution has emerged as a practical method for protein structural modeling by providing structural contact information from alignments of amino acid sequences. In parallel, chemical cross‐linking/mass spectrometry (XLMS) has gained attention as a universally applicable method for obtaining low‐resolution distance const...

In this work, we discuss the challenging time-resolved fluorescence anisotropy of subtilisin Carlsberg (SC), which contains a single Trp residue and is a model fluorescence system. Experimental decay rates and quenching data suggest that the fluorophore should be exposed to water, but the Trp is partially buried in a hydrophobic pocket in the cryst...

Invasive opportunistic fungal infections and antifungal drug resistance prompt the investigation of the underlying molecular mechanisms of the inhibition of the triazole drugs. The target of triazoles is the product of the ERG11 gene, the cytochrome P450 sterol 14α-demethylase (CYP51), which is part of the ergosterol biosynthetic pathway. In this s...

A software was developed to evaluate structural models using chemical crosslinking experiments. The user provides the types of linkers used and their reactivity, and the observed crosslinks and dead-ends. The software computes the minimum length of a physically-inspired linker that connects the reactive atoms of interest, and reports the consistenc...

Motivation: Chemical cross-linking/mass spectrometry (XLMS) is an experimental method to obtain distance constraints between amino acid residues which can be applied to structural modeling of tertiary and quaternary biomolecular structures. These constraints provide, in principle, only upper limits to the distance between amino acid residues along...

The analysis of coevolutionary signals from families of evolutionarily related sequences is a recent conceptual framework that provides valuable information about unique intramolecular interactions and, therefore, can assist in the elucidation of biomolecular conformations. It is based on the idea that compensatory mutations at specific residue pos...

Undergraduate experiments on ionic conductivity are common practice in general chemistry and advanced physical chemistry laboratories. Often, the conductivities are measured for solutions prepared for various salts, in a range of concentrations, and the relationship between solution conductivity and concentration is interpreted in terms of the Kohl...

Motivation: The majority of the inter-residue distances in a protein structure are correlated given a fixed topology. Here, we investigate whether we are able to predict a structure’s folding rate, which is known to depend on the complexity of its fold, while considering only a small, uncorrelated fraction of its contacts. Results: We define an...

Here, a force-field designed to represent XLMS-derived constraints is proposed. The potential energy functions are obtained by computing, in the database of known protein structures, the probability of satisfaction of a topological cross-linking distance as a function of the Euclidean distance between amino acid residues. The force-field can be eas...

div> Chemical cross-linking/Mass Spectrometry (XLMS) is an experimental method to obtain distance constraints between amino acid residues, which can be applied to structural modeling of tertiary and quaternary biomolecular structures. These constraints provide, in principle, only upper limits to the distance between amino acid residues along the su...

Motivation: Elucidation of protein native states from amino acid sequences is a primary computational challenge. Modern computational and experimental methodologies, such as molecular coevolution and chemical cross-linking mass-spectrometry allowed protein structural characterization to previously intangible systems. Despite several independent su...

Fluorescence spectroscopy is an important method to study protein conformational dynamics and solvation structures. Tryptophan (Trp) residues are the most important and practical intrinsic probes for protein fluorescence due to the variability of their fluorescence wavelengths: Trp residues emit in wavelengths ranging from 308 to 360 nm depending o...

Lipases are water-soluble enzymes which catalyze the hydrolysis of lipids. Since lipids are mostly hydrophobic, lipase activity occur preferentially at interfaces of aqueous and organic phases. In this work, we study the molecular mechanisms by which the Burkholderia cepacia lipase (BCL) is activated at interfaces of water with octane and with meth...

Preferential solvation is a fundamental parameter for the interpretation of solubility and solute structural stability. The molecular basis for solute-solvent interactions can be obtained through distribution functions, and the thermodynamic connection to experimental data depends on the computation of distribution integrals, specifically Kirkwood-...

Motivation: The flow of vibrational energy in proteins has been shown not to obey expectations for isotropic media. The existence of preferential pathways for energy transport, with probable connections to allostery mechanisms, has been repeatedly demonstrated. Here, we investigate whether, by representing a set of protein structures as networks o...

Increasing the stability of proteins is important for their application in industrial processes. In the intracellular environment many small molecules, called osmolytes, contribute to protein stabilization under physical or chemical stress. Understanding the nature of the interactions of these osmolytes with proteins can help the design of solvents...

The Edema Factor (EF) is one of three major toxins of Anthrax. EF is an adenylyl cyclase that disrupts cell signaling by the accelerated conversion of ATP to cyclic-AMP. EF has a much higher catalytic rate than mammalian adenylyl cyclases (mACs). Crystal structures were obtained for mACs and for EF, but the molecular basis for the different catalyt...

Nuclear hormone receptors (NR) are transcription factors that activate gene expression in response to ligands. Structural and functional studies of the ligand binding domains (LBD) of NRs revealed that the dynamics of their C-terminal helix (H12) is fundamental for NR activity. H12 is rigid and facilitates binding of coactivator proteins in the ago...

The Molecular Packing problem consists in determining a molecular arrangement satisfying a given set of spatial constraints related to the geometry and distance between atoms of different molecules. The result of a solution to the MP problem is a box filled with molecules at valid coordinates that satisfies energy distribution constraints and is re...

The protein folding (Levinthal’s) paradox states that it would not be possible in a physically meaningful time to a protein to reach the native (functional) conformation by a random search of the enormously large number of possible structures. This paradox has been solved: it was shown that small biases toward the native conformation result in real...

Thyroid hormone receptors (TRs) are members of the nuclear receptor (NR) superfamily of ligand-activated transcription factors involved in cell differentiation, growth, and homeostasis. Although X-ray structures of many NR ligand binding domains (LBD) reveal that the ligand binds within the hydrophobic core of the ligand binding pocket (LBP), a few...

Cellobiohydrolases hydrolyze cellulose releasing cellobiose units. They are very important for a number of biotechnological applications, such as, for example, production of cellulosic ethanol and cotton fiber processing. The Trichoderma cellobiohydrolase I (CBH1 or Cel7A) is an industrially important exocellulase. It exhibits a typical two domain...

Edema Factor (EF) is a component of Bacillus anthracis toxin essential for virulence. Its adenylyl cyclase activity is induced by complexation with the ubiquitous eukaryotic cellular protein, calmodulin (CaM). EF and its complexes with CaM, nucleotides and/or ions, have been extensively characterized by X-ray crystallography. Those structural data...

Thiazolidinediones (TZDs) act through peroxisome proliferator activated receptor (PPAR) γ to increase insulin sensitivity in type 2 diabetes (T2DM), but deleterious effects of these ligands mean that selective modulators with improved clinical profiles are needed. We obtained a crystal structure of PPARγ ligand binding domain (LBD) and found that t...

Supercritical carbon dioxide is a promising green-chemistry solvent for many enzyme-catalyzed chemical reactions, yet the striking stability of some enzymes in such unconventional environments is not well understood. Here, we investigate the stabilization of the Candida antarctica Lipase B (CALB) in supercritical carbon dioxide-water biphasic syste...

Hb S-São Paulo (SP) [HBB:c.20A>T p.Glu6Val; c.196A>G p.Lys65Glu] is a new double-mutant hemoglobin that was found in heterozygosis in an 18-month-old Brazilian male with moderate anemia. It behaves like Hb S in acid electrophoresis, isoelectric focusing and solubility testing but shows different behavior in alkaline electrophoresis, cation-exchange...

The simulation of protein unfolding usually requires recording long molecular dynamics trajectories. The present work aims to figure out whether NMR restraints data can be used to probe protein conformations in order to accelerate the unfolding simulation. The SH3 domain of nephrocystine (nph SH3) was shown by NMR to be destabilized by point mutati...

Unveiling the mechanisms of energy relaxation in biomolecules is key to our understanding of protein stability, allostery, intramolecular signaling, and long-lasting quantum coherence phenomena at ambient temperatures. Yet, the relationship between the pathways of energy transfer and the functional role of the residues involved remains largely unkn...

Glycosyl hydrolases are enzymes capable of breaking the glycosidic linkage of polysaccharides and have considerable industrial and biotechnological applications. Driven by the later applications, it is frequently desirable that glycosyl hydrolases display stability and activity under extreme environment conditions, such as high temperatures and ext...

We develop a CHARMM-based interaction potential for rosiglitazone, a well-known selective ligand to the γ isoform of the peroxisome proliferator-activated receptor (PPARγ) and widely marketed antidiabetic drug of the thiazolidinedione (TZD) class. We derive partial atomic charges and dihedral torsion potentials for seven rotations in the molecule,...

The anthrax edema factor is a toxin overproducing damaging levels of cyclic adenosine monophosphate (cAMP) and pyrophosphate (PPi) from ATP. Here, mechanisms of dissociation of ATP and products (cAMP, PPi) from the active site are studied using locally enhanced sampling (LES) and steered molecular dynamics simulations. Various substrate conformatio...

Thyroid hormone receptors (TRs) are ligand-gated transcription factors with critical roles in development and metabolism. Although x-ray structures of TR ligand-binding domains (LBDs) with agonists are available, comparable structures without ligand (apo-TR) or with antagonists are not. It remains important to understand apo-LBD conformation and th...

An inexact restoration (IR) approach is presented to solve a matricial optimization problem arising in electronic structure calculations. The solution of the problem is the closed-shell density matrix and the constraints are represented by a Grassmann manifold. One of the mathematical and computational challenges in this area is to develop methods...

Understanding the molecular basis of the binding modes of natural and synthetic ligands to nuclear receptors is fundamental to our comprehension of the activation mechanism of this important class of hormone regulated transcription factors and to the development of new ligands. Thyroid hormone receptors (TR) are particularly important targets for p...

Calmodulin (CaM) is a remarkably flexible protein which can bind multiple targets in response to changes in intracellular calcium concentration. It contains four calcium-binding sites, arranged in two globular domains. The calcium affinity of CaM N-terminal domain (N-CaM) is dramatically reduced when the complex with the edema factor (EF) of Bacill...

The characterization of a coffee gene encoding a protein similar to miraculin-like proteins, which are members of the plant Kunitz serine trypsin inhibitor (STI) family of proteinase inhibitors (PIs), is described. PIs are important proteins in plant defence against insects and in the regulation of proteolysis during plant development. This gene ha...

The ligand binding domain (LBD) of nuclear hormone receptors adopts a very compact, mostly alpha-helical structure that binds specific ligands with very high affinity. We use circular dichroism spectroscopy and high-temperature molecular dynamics simulations to investigate unfolding of the LBDs of thyroid hormone receptors (TRs). A molecular descri...

The Edema Factor (EF), one of the virulence factors of anthrax, is an adenylyl cyclase that promotes the overproduction of cyclic-AMP (cAMP) from ATP, and therefore perturbs cell signaling. Crystallographic structures of EF bound to ATP analogs and reaction products, cyclic-AMP, and Pyrophosphate (PPi), revealed different substrate conformations an...

Nuclear receptors are important targets for pharmaceuticals, but similarities between family members cause difficulties in obtaining highly selective compounds. Synthetic ligands that are selective for thyroid hormone (TH) receptor beta (TRbeta) vs. TRalpha reduce cholesterol and fat without effects on heart rate; thus, it is important to understan...

Given r real functions F 1(x),...,F r (x) and an integer p between 1 and r, the Low Order-Value Optimization problem (LOVO) consists of minimizing the sum of the functions that take the p smaller values. If (y 1,...,y r ) is a vector of data and T(x, t i ) is the predicted value of the observation i with the parameters x Î IRnx \in I\!\!R^n , it...

Estrogen Receptor (ER) is an important target for pharmaceutical design. Like other ligand-dependent transcription factors, hormone binding regulates ER transcriptional activity. Nevertheless, the mechanisms by which ligands enter and leave ERs and other nuclear receptors remain poorly understood. Here, we report results of locally enhanced samplin...

Thyroid receptors, TRalpha and TRbeta, are involved in important physiological functions such as metabolism, cholesterol level and heart activities. Whereas metabolism increase and cholesterol level lowering could be achieved by TRbeta isoform activation, TRalpha activation affects heart rates. Therefore, beta-selective thyromimetics have been deve...

Many algorithms exist for protein structural alignment, based on internal protein coordinates or on explicit superposition of the structures. These methods are usually successful for detecting structural similarities. However, current practical methods are seldom supported by convergence theories. In particular, although the goal of each algorithm...

Structural Alignment is an important tool for fold identification of proteins, structural screen-ing on ligand databases, pharmacophore identification and other applications. In the general case, the optimization problem of superimposing two structures is nonsmooth and noncon-vex, so that most popular methods are heuristic and do not employ derivat...

Steered molecular dynamics simulations of ligand dissociation from Thyroid hormone receptors indicate that dissociation is favored via rearrangements in a mobile part of the LBD comprising H3, the loop between H1 and H2, and nearby beta-sheets, contrary to current models in which the H12 is mostly involved. Dissociation is facilitated in this path...

A theory of globally convergent trust-region methods for self-consistent field electronic structure calculations that use the density matrices as variables is developed. The optimization is performed by means of sequential global minimizations of a quadratic model of the true energy. The global minimization of this quadratic model, subject to the i...

Nuclear receptor (NR) ligands occupy a pocket that lies within the core of the NR ligand-binding domain (LBD), and most NR LBDs lack obvious entry/exit routes upon the protein surface. Thus, significant NR conformational rearrangements must accompany ligand binding and release. The precise nature of these processes, however, remains poorly understo...

As far as more complex systems are being accessible for quantum chemical calculations, the reliability of the algorithms used becomes increasingly important. Trust-region strategies comprise a large family of optimization algorithms that incorporates both robustness and applicability for a great variety of problems. The objective of this work is to...

We present a review on the intermolecular dynamics of liquid aqueous systems focusing mainly on Molecular Dynamics simulation work that has been carried out at the State University of Campinas in recent years. Emphasis is given on simulation results that are more directly related to modern experimental spectroscopic measurements.

Alumina and 1:1 mixed oxides of Al2O3–ZrO2, Al2O3–TiO2, SiO2–TiO2 and ZrO2–TiO2 were synthesized via a sol–gel process by the so-called neutral amine route, followed by calcination at 600 °C. The mixed oxides were characterized before calcination by X-ray diffraction, revealing ordered hexagonal (Al2O3, Al2O3–ZrO2, ZrO2–TiO2) and lamellar (SiO2–TiO...

Molecular Dynamics is a powerful methodology for the comprehension at molecular level of many chemical and biochemical systems. The theories and techniques developed for structural and thermodynamic analyses are well established, and many software packages are available. However, designing starting configurations for dynamics can be cumbersome. Eas...

This paper describes the synthesis, characterization and a thermogravimetric (t.g.) study of 11 adducts of general formula MCl2·nL (M = Cu, Co and Sn; n = 1 and 2 for Sn, and 2 for Cu and Co; L = ethyleneurea eu, ethylenethiourea etu, and propyleneurea pu). The i.r. results shows that the eu and pu adducts are coordinated through oxygen, whereas fo...

Complexes of formula CuCl2 2arg and CuCl2 4ala (arg = arginine; ala = alanine) were prepared at room temperature by a solid state route. The metal–amino acid solid state interactions were studied by i.r. spectroscopy and solution calorimetry. For both complexes, participation of the carboxylate group as well as nitrogen in coordination are inferred...

Adducts of the general formula CuCl2·nlys (n=1, 2, 4; lys=lysine) and CuCl2·ngly (n=2, 4; gly=glycine) were prepared by reacting the ligands with CuCl2 in solid state. The adducts were characterized by elemental analysis, infrared spectroscopy and thermogravimetry. In all cases, the cation is coordinated to the amino acids via amino and carbonyl gr...

In this work we report on the synthesis, characterization and thermal behavior of 18 adducts of general formula CdX2·nL (where X=Cl, Br and I, n=1 and 2, and L=ethyleneurea (eu), ethylenethiourea (etu) and propyleneurea (pu)). The IR spectroscopy results shows that for the eu and pu adducts, coordination occurs through oxygen, whereas for etu, nitr...

Lamellar silica and cadmium or mercury derivative-doped samples were synthesized by neutral amine route through the sol–gel process. These samples showed a decrease of the interlamellar d-space promoted only by an increase of the externally applied pressure on the samples. For a constant external pressure the observed decrease has a linear behavior...