
Patrícia FN FaíscaUniversity of Lisbon | UL · Department of Physics and BioISI
Patrícia FN Faísca
PhD, Physics
Assistant Professor with Habilitation (Agregação) and Group Leader
About
92
Publications
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Introduction
"The physicists won't like me because I'm a renegade from physics...and the chemists won't like me because I'm a physicist. And the biologists won't like me because I do biology. And the mathematicians won't know about me because I don't do mathematics" - C.P. Snow
Additional affiliations
December 2013 - present
March 2007 - January 2008
February 2008 - December 2013
Education
January 1999 - September 2002
September 1997 - September 1998
October 1994 - December 1996
Publications
Publications (92)
We have come a long way since coining of the term protein and the early findings that proteins are charged macromolecules composed of strings of amino acids linked by peptide bonds. Today, structural biologists have technologies that allow in many cases to achieve an atomic-level understanding of protein structure, dynamics and folding; protein phy...
There is growing support for the idea that the in vivo folding process of knotted proteins is assisted by chaperonins, but the mechanism of chaperonin-assisted folding remains elusive. Here, we conduct extensive Monte Carlo simulations of lattice and off-lattice models to explore the effects of confinement and hydrophobic intermolecular interaction...
Protein β2-microglobulin is the causing agent of two amyloidosis, dialysis related amyloidosis (DRA), affecting the bones and cartilages of individuals with chronic renal failure undergoing long-term hemodialysis, and a systemic amyloidosis, found in one French family, which impairs visceral organs. The protein’s small size and its biomedical signi...
Monte Carlo simulations are a powerful technique and are widely used in different fields. When applied to complex molecular systems with long chains, such as those in synthetic polymers and proteins, they have the advantage of providing a fast and computationally efficient way to sample equilibrium ensembles and calculate thermodynamic and structur...
The D76N mutant of the β 2 m protein is a biologically motivated model system to study protein aggregation. There is strong experimental evidence, supported by molecular simulations, that D76N populates a highly dynamic conformation (which we originally named I 2 ) that exposes aggregation-prone patches as a result of the detachment of the two term...
Atomic force microscopy (AFM) imaging enables the visualization of protein molecules with high resolution, providing insights into their shape, size, and surface topography. Here, we use AFM to study the aggregation process of protein S100A9 in physiological conditions, in the presence of calcium at a molar ratio 4Ca 2+ :S100A9. We find that S100A9...
Knotted proteins are present in nature, but there is
still an open issue regarding the existence of a universal role for
these remarkable structures. To address this question, we used
classical molecular dynamics (MD) simulations combined with in
vitro experiments to investigate the role of the Gordian knot in the
catalytic activity of UCH-L1. To c...
The last years have witnessed remarkable advances in our understanding of the emergence and consequences of topological constraints in biological and soft matter. Examples are abundant in relation to (bio)polymeric systems and range from the characterization of knots in single polymers and proteins to that of whole chromosomes and polymer melts. At...
The field of protein science is witnessing a revolution in the wake of recent breakthroughs such as the artificial intelligence (AI) system AlphaFold which can predict the three-dimensional structure of almost every globular protein from its protein sequence alone. Inevitably, there is some expectation that structure-prediction modelling approaches...
Determining the role of non-native interactions in folding dynamics, kinetics, and mechanisms is a classic problem in protein folding. More
recently, this question has witnessed a renewed interest in light of the hypothesis that knotted proteins require the assistance of non-native
interactions to fold efficiently. Here, we conduct extensive equili...
Determining the role of non-native interactions in folding dynamics, kinetics and mechanisms is a classical problem in protein folding. More recently, this question has witnessed a renewed interest in light of the hypothesis that knotted proteins require the assistance of non-native interactions to fold efficiently. Here, we conducted extensive equ...
Protein aggregation is a complex process, strongly dependent on environmental conditions and highly structurally heterogeneous, both at the final level of fibril structure and intermediate level of oligomerization. Since the first step in aggregation is the formation of a dimer, it is important to clarify how certain properties of the latter (e.g.,...
Protein aggregation is a complex process that strongly depends on environmental conditions and has considerable structural heterogeneity, not only at the level of fibril structure but also at the level of molecular oligomerization. Since the first step in aggregation is the formation of a dimer, it is important to clarify how certain properties (e....
This introductory textbook provides a synthetic overview of the laws and formal aspects of thermodynamics and was designed for undergraduate students in physics, and in the physical sciences. Language and notation have been kept as simple as possible throughout the text.
While this is a self-contained text on thermodynamics (i.e. focused on macros...
Protein beta-2-microglobulin (β2m) is classically considered the causative agent of dialysis related amyloidosis, a conformational disorder that affects patients undergoing long-term hemodialysis. The wild type (WT) form, the ΔN6 structural variant, and the D76N mutant have been extensively used as model systems of β2m aggregation. In all of them,...
Native interactions are crucial for folding, and non-native interactions appear to be critical for efficiently knotting proteins. Therefore, it is important to understand both their roles in the folding of knotted proteins. It has been proposed that non-native interactions drive the correct order of contact formation, which is essential to avoid ba...
Protein beta-2-microglobulin (β2m) is classically considered the causative agent of dialysis related amyloidosis (DRA), a conformational disorder that affects patients undergoing long-term hemodialysis. Together with the wild type form, the ΔN6 structural variant, and the D76N mutant, have been extensively used as model systems of β2m aggregation....
A small fraction of all protein structures characterized so far are entangled. The challenge of understanding the properties of these knotted pro- teins, and the why and the how of their natural folding process, has been taken up in the past decade with different approaches, such as structural character- ization, in vitro experiments, and simulatio...
Human β2-microglobulin (b2m) protein is classically associated with dialysis-related amyloidosis (DRA). Recently, the single point mutant D76N was identified as the causative agent of a hereditary systemic amyloidosis affecting visceral organs. To get insight into the early stage of the β2m aggregation mechanism, we used molecular simulations to pe...
In the summer of 2018, Professor Michael Kosterlitz visited Portugal as a plenary speaker of the FÍSICA2018 conference organised by the Portuguese Physical Society (SPF) and by the University of Beira Interior. FÍSICA 2018 comprised two meetings: the 28th Iberian Meeting for Physics Teaching, and the 21st National Conference of Physics, a biannual...
A small fraction of all protein structures characterized so far are entangled. The challenge of understanding the properties of these knotted proteins, and the why and the how of their natural folding process, has been taken up in the past decade with different approaches, such as structural characterization, in vitro experiments, and simulations o...
A small fraction of all protein structures characterized so far are entangled. The challenge of understanding the properties of these knotted proteins, and the why and the how of their natural folding process, has been taken up in the past decade with different approaches, such as structural characterization, in vitro experiments, and simulations o...
This snapshot volume is designed to provide a smooth entry into the field of protein folding. Presented in a concise manner, each section introduces key concepts while providing a brief overview of the relevant literature. Outlook subsections will pinpoint specific aspects related to emerging methodologies, concepts and trends.
The identification of intermediate states for folding and aggregation is important from a fundamental standpoint and for the design of novel therapeutic strategies targeted at conformational disorders. Protein human β2-microglobulin (HB2m) is classically associated with dialysis related amyloidosis, but the single point mutant D76N was recently ide...
The chaperonin complex GroEL-GroES is able to accelerate the folding process of knotted proteins considerably. However, the folding mechanism inside the chaperonin cage is elusive. Here we use a combination of lattice and off-lattice Monte Carlo simulations of simple Gō models to study the effect of physical confinement and local flexibility on the...
We employed high-temperature classical molecular dynamics (MD) simulations to investigate the unfolding process of the wild-type (WT) and F508del-NBD1 domains of CFTR protein, with and without second-site mutations. To rationalize the in vitro behavior of F508del-NBD1, namely its lower folding yield and higher aggregation propensity, we focused our...
Abstract Knotted proteins have their native structures arranged in the form of an open knot. In the last ten years researchers have been making significant efforts to reveal their folding mechanism and understand which functional advantage(s) knots convey to their carriers. Molecular simulations have been playing a fundamental role in this endeavor...
This work investigates the role of N- to C- termini coupling in the folding transition of small, single domain proteins via extensive Monte Carlo simulations of both lattice and off-lattice models. The reported results provide compelling evidence that the existence of native interactions between the terminal regions of the polypeptide chain (i.e. t...
The folding properties of a protein whose native structure contains a 52 knot are investigated by means of extensive Monte Carlo simulations of a simple lattice model and compared with those of a 31 knot. A 52 knot embedded in the native structure enhances the kinetic stability of the carrier lattice protein in a way that is clearly more pronounced...
Author Summary
Dialysis-related amyloidosis (DRA) is a conformational disease that affects individuals undergoing long-term haemodialysis. In DRA the progressive accumulation of protein human β2-microglobulin (Hβ2m) in the osteoarticular system, followed by its assembly into amyloid fibrils, eventually leads to tissue erosion and destruction. Discl...
This work explores the impact of knots, knot depth and motif of the threading terminus in protein folding properties (kinetics, thermodynamics and mechanism) via extensive Monte Carlo simulations of lattice models. A knotted backbone has no effect on protein thermodynamic stability but it may affect key aspects of folding kinetics. In this regard,...
Alternative folding pathway for kd. In this folding pathway the knotting of the protein backbone occurs in conformations with Q = 0.33.
(TIFF)
Native contact maps and native structures. The region of the native structures colored in grey represent the original native structures k0 and u0 from which we constructed kd (a) and ud (b) by extending both termini, and the other model systems by extending the termini closest to the knotted core (colored green). The extended termini are colored in...
Pathway in kh3 leading to misfolded conformations. In these misfolded conformations the threading terminus docks onto the other terminus forming native contacts that stabilize the conformation.
(TIFF)
Formation of misfolded conformations in kd due to incorrect threading of the terminus.
(TIFF)
Formation of misfolded conformations in kd due to incorrect threading of the terminus.
(TIFF)
We use molecular dynamics simulations of a full atomistic Gō model to explore the impact of selected DE-loop mutations (D59P and W60C) on the folding space of protein human β2-microglobulin (Hβ2m), the causing agent of dialysis-related amyloidosis, a conformational disorder characterized by the deposition of insoluble amyloid fibrils in the osteoar...
Electrostatic isocontours of the WT native (N)—X-ray structure—and intermediate (I)—clustering representative—states in acidic (4.0) and neutral pH (7.0) conditions. Coloring from red to blue corresponds to electrostatic potentials of −5 to +5 kBT. The 21 hydrophobic core amino acids are represented in pink in the SASA representation/depiction of t...
Additional structural traits of the intermediate state identified for the three Hβ2m variants. The graph displays on the left-hand side the distributions of Cα RMSD values of the core region, comprehended between β-strands B and F (residues 22–83), after fitting it to the corresponding native structure core. The right-hand side depicts the distribu...
Three-dimensional structures of the scarcely-populated native-like species identified for two of the Hβ2m variants fitted to the original X-ray native structure. The (starting) N-terminus is colored in blue while the C-terminus is shown in red.
Native contact maps of the intermediate state identified for each of the three Hβ2m variants. Bottom half: Native contacts by residue in the native state. Top half: Probability map of the ratios between the total number of native atomic contacts by pair of residues in the intermediate and native states.
One of the major components of amyloid plaques of patients with dialysis-related amyloidosis (DRA) is a cleaved variant of protein β2-microglubulin (hβ2m), ΔN6, which lacks six N-terminal residues. In vitro experiments showed that contrary to the wild-type form, ΔN6 is able to form amyloid fibrils at physiological pH. Furthermore, a mild acidificat...
We performed extensive lattice Monte Carlo simulations of ribosome-bound stalled nascent chains (RNCs) to explore the relative roles of native topology and non-native interactions in co-translational folding of small proteins.We found that the formation of a substantial part of the native structure generally occurs towards the end of protein synthe...
We assessed the interplay of native topology and non-native interactions on surface-tethered protein folding via extensive Monte Carlo simulations of a simple lattice model. In particular, we investigated the thermodynamics and kinetics of protein-like sequences enclosing different amounts of non-native interactions to protein energetics, and which...
We explore the effect of surface tethering on the folding process of a lattice protein that contains a trefoil knot in its native structure via Monte Carlo simulations. We show that the outcome of the tethering experiment depends critically on which terminus is used to link the protein to a chemically inert plane. In particular, if surface tetherin...
Mean number of established non-native contacts as a function of the fraction of established native contacts, Q. (A) for the knotted protein and (B) for the unknotted one. To compute these curves we have extracted the relevant data from the set of folding trajectories that were used to evaluate the folding rate (Figure 5). Essentially, we grouped th...
Alternative folding pathway for kh3. Here and in the following figures each displayed conformation with fraction of native contacts Q is the closest to the cluster's centroid, i.e., the cluster's representative. The residues colored in yellow have at least two of its native contacts formed. In parenthesis we report the ratio between the size of the...
Another folding pathway leading to dead-end conformations when the chain is tethered to the surface via the C-terminus. Each conformation with fraction of native contacts Q is the closest to the cluster’s centroid, i.e., the cluster’s representative. The residues coloured in orange have at least two of its native contacts formed. In parenthesis we...
Alternative knotting mechanism operating in the bulk. Each conformation with fraction of native contacts Q is the closest to the cluster’s centroid, i.e., the cluster’s representative. The residues colored in orange have at least two of its native contacts formed. In parenthesis we show the ratio between the size of the cluster (its number of confo...
Comparison of the folding rates in the surface-tethered setups and in the point-tethered setups.
(TIFF)
Pathway leading to dead-end conformations when the chain is tethered to the surface via the N-terminus. Each conformation with fraction of native contacts Q is the closest to the cluster’s centroid, i.e., the cluster’s representative. The residues colored in orange have at least two of its native contacts formed. In parenthesis we show the ratio be...
Probability map in the dominant cluster of conformations with fraction of native contacts Q = 0.75 populated by the knotted protein when it is linked to the plane by its N-terminus. The probability map shows the mean averaged probability of occurrence of each established contact (native and non-native). Also shown (inset) is cluster’s representativ...
Gō models are exceedingly popular tools in computer simulations of protein folding. These models are native-centric, i.e., they are directly constructed from the protein's native structure. Therefore, it is important to understand up to which extent the atomistic details of the native structure dictate the folding behavior exhibited by Gō models. H...
We compared the folding pathways of selected mutational variants of the α-spectrin SH3 domain (Spc-SH3) by using a continuum model that combines a full atomistic protein representation with the Gō potential. Experimental data show that the N47G mutant shows very little tendency to aggregate while the N47A and triple mutant D48G(2Y) are both amyloid...
For almost 15 years, the experimental correlation between protein folding rates and the contact order parameter has been under scrutiny. Here, we use a simple simulation model combined with a native-centric interaction potential to investigate the physical roots of this empirical observation. We simulate a large set of circular permutants, thus eli...
Systematic Monte Carlo simulations of simple lattice models show that the final stage of protein folding is an ordered process where native contacts get locked (i.e., the residues come into contact and remain in contact for the duration of the folding process) in a well-defined order. The detailed study of the folding dynamics of protein-like seque...
We perform extensive lattice Monte Carlo simulations of protein folding to construct and compare the equilibrium and the kinetic transition state ensembles of a model protein that folds to the native state with two-state kinetics. The kinetic definition of the transition state is based on the folding probability analysis method, and therefore on th...
We carry out systematic Monte Carlo simulations of Gō lattice proteins to investigate and compare the folding processes of two model proteins whose native structures differ from each other due to the presence of a trefoil knot located near the terminus of one of the protein chains. We show that the folding time of the knotted fold is larger than th...
The nucleation mechanism of protein folding, originally proposed by Baldwin in the early 1970s, was firstly observed by Shakhnovich and co-workers two decades later in the context of Monte Carlo simulations of a simple lattice model. At about the same time the extensive use of φ-value analysis provided the first experimental evidence that the foldi...
In protein folding the term plasticity refers to the number of alternative folding pathways encountered in response to free energy perturbations such as those induced by mutation. Here we explore the relation between folding plasticity and a gross, generic feature of the native geometry, namely, the relative number of local and non-local native con...
We apply a simulational proxy of the phi-value analysis and perform extensive mutagenesis experiments to identify the nucleating residues in the folding "reactions" of two small lattice Go polymers with different native geometries. Our findings show that for the more complex native fold (i.e., the one that is rich in nonlocal, long-range bonds), mu...
We perform extensive Monte Carlo simulations of a lattice model and the Gō potential [N. Gō and H. Taketomi, Proc. Natl. Acad. Sci. U.S.A. 75, 559563 (1978)] to investigate the existence of folding pathways at the level of contact cluster formation for two native structures with markedly different geometries. Our analysis of folding pathways reveal...
Protein structure and stability rely on the interplay of a large number of weak molecular interactions working in concert to assure a stable and unique native fold. Throughout evolution, different strategies have been devised to modulate protein conformational stability and enhance function and survival of proteins even under adverse conditions. Th...
For the vast majority of naturally occurring, small, single domain proteins folding is often described as a two-state process that lacks detectable intermediates. This observation has often been rationalized on the basis of a nucleation mechanism for protein folding whose basic premise is the idea that after completion of a specific set of contacts...
The folding of naturally occurring, single-domain proteins is usually well described as a simple, single-exponential process lacking significant trapped states. Here we further explore the hypothesis that the smooth energy landscape this implies, and the rapid kinetics it engenders, arises due to the extraordinary thermodynamic cooperativity of pro...
Monte Carlo simulations show that long-range interactions play a major role in determining the folding rates of 48-mer three-dimensional lattice polymers modeled by the Gō potential. For three target structures with different native geometries we found a sharp increase in the folding time when the relative contribution of the long-range interaction...
We review some of our recent results obtained within the scope of simple lattice models and Monte Carlo simulations that illustrate the role of native geometry in the folding kinetics of two state folders.
In this paper, we investigate the role of native geometry on the kinetics of protein folding based on simple lattice models and Monte Carlo simulations. Results obtained within the scope of the Miyazawa-Jernigan indicate the existence of two dynamical folding regimes depending on the protein chain length. For chains larger than 80 amino acids, the...
Monte Carlo simulations of a Miyazawa-Jernigan lattice-polymer model indicate that, depending on the native structure's geometry, the model exhibits two broad classes of folding mechanisms for two-state folders. Folding to native structures of low contact order is driven by backbone distance and is characterized by a progressive accumulation of str...
The present work completes the study of the conditions under which Melnikov method can be used when the unperturbed system has a parabolic periodic orbit with a homoclinic loop, by considering the case of orbits whose associated Poicar map has linear part equal to the identity. The result is that the conditions for the persistence under perturbatio...
Monte Carlo simulations of protein folding show the emergence of a strong correlation between the relative contact order parameter, CO, and the folding time, t, of two-state folding proteins for longer chains with number of amino acids, N>=54, and higher contact order, CO > 0.17. The correlation is particularly strong for N=80 corresponding to slow...
Monte Carlo simulations of a simple lattice model of protein folding show two distinct regimes depending on the chain length. The first regime well describes the folding of small protein sequences and its kinetic counterpart appears to be single exponential in nature, while the second regime is typical of sequences longer than 80 amino acids and th...