Leandro Garcia - Academia.edu (original) (raw)
Papers by Leandro Garcia
Transport Policy, 2007
One of the key questions in the evaluation of transport policies and investment decisions is the ... more One of the key questions in the evaluation of transport policies and investment decisions is the valuation of the time savings or losses arising from such decisions. This paper uses the stated preference method to determine the value of time in a given traffic context characterised by a road parallel network. The values obtained are higher than usual in Spanish project evaluation which, among other things, points out the need for specific studies of all transport projects whenever possible. Finally, two cases are described which illustrate the relevance of the value of time. The first evaluates time savings related to the pricing policies of a motorway competing with a trunk road. The second establishes the minimum amount of traffic that justifies the replacement of a single carriageway by a dual carriageway. r
Physical Review E, 2005
Conformational restrictions imposed by hydrogen bond formation during protein folding are investi... more Conformational restrictions imposed by hydrogen bond formation during protein folding are investigated by Monte Carlo simulations of a non-native-centric, two-dimensional, hydrophobic model in which the formation of favorable contacts is coupled to an effective reduction in lattice coordination. This scheme is intended to mimic the requirement that polar backbone groups of real proteins must form hydrogen bonds concomitantly to their burial inside the apolar protein core. In addition to the square lattice, with z = 3 conformations per monomer, we use extensions in which diagonal step vectors are allowed, resulting in z = 5 and z = 7. Thermodynamics are governed by the hydrophobic energy function, according to which hydrophobic monomers tend to make contacts unspecifically while the reverse is true for hydrophilic monomers, with the additional restriction that only contacts between monomers adopting one of z h Ͻ z local conformations contribute to the energy, where z h is the number of local conformations assumed to be compatible with hydrogen bond formation. The folding transition abruptness and van't Hoff-to-calorimetric-enthalpy ratio are found to increase dramatically by this simple and physically motivated mechanism. The observed increase in folding cooperativity is correlated to an increase in the convexity of the underlying microcanonical conformational entropy as a function of energy. Preliminary simulations in three dimensions, even though using a smaller relative reduction in lattice effective coordination z h / z =4/5, display a slight increase in cooperativity for a hydrophobic model of 40 monomers and a more pronounced increase in cooperativity for a native-centric Go-model with the same native conformation, suggesting that this purely entropic effect is not an artifact of dimensionality and is likely to be of fundamental importance in the theoretical understanding of folding cooperativity.
Proteins-structure Function and Bioinformatics, 2006
Monte Carlo simulations of a hydrophobic protein model of 40 monomers in the cubic lattice are us... more Monte Carlo simulations of a hydrophobic protein model of 40 monomers in the cubic lattice are used to explore the effect of energetic frustration and interaction heterogeneity on its folding pathway. The folding pathway is described by the dependence of relevant conformational averages on an appropriate reaction coordinate, pfold, defined as the probability for a given conformation to reach the native structure before unfolding. We compare the energetically frustrated and heterogeneous hydrophobic potential, according to which individual monomers have a higher or lower tendency to form contacts unspecifically depending on their hydrophobicities, to an unfrustrated homogeneous Go-type potential with uniformly attractive native interactions and neutral non-native interactions (called Go1 in this study), and to an unfrustrated heterogeneous potential with neutral non-native interactions and native interactions having the same energy as the hydrophobic potential (called Go2 in this study). Folding kinetics are slowed down dramatically when energetic frustration increases, as expected and previously observed in a two-dimensional model. Contrary to our previous results in two dimensions, however, it appears that the folding pathway and transition state ensemble can be significantly dependent on the energy function used to stabilize the native structure. The sequence of events along the reaction coordinate, or the order along this coordinate in which different regions of the native conformation become structured, turns out to be similar for the hydrophobic and Go2 potentials, but with analogous events tending to occur at lower pfold values in the first case. In particular, the transition state obtained from the ensemble around pfold = 0.5 is more structured for the hydrophobic potential. For Go1, not only the transition state ensemble but the order of events itself is modified, suggesting that interaction heterogeneity, in addition to energetic frustration, can have significant effects on the folding mechanism, most likely by modifying the probability of different contacts in the unfolded state, the starting point for the folding reaction. Although based on a simple model, these results provide interesting insight into how sequence-dependent switching between folding pathways might occur in real proteins.
Physical Review E, 2001
We show that a nonspecific hydrophobic energy function can produce proteinlike folding behavior o... more We show that a nonspecific hydrophobic energy function can produce proteinlike folding behavior of a three-dimensional protein model of 40 monomers in the cubic lattice when the native conformation is chosen judiciously. We confirm that monomer inside/outside segregation is a powerful criterion for the selection of appropriate structures, an idea that was recently proposed with basis on a general theoretical analysis and simulations of much simpler two-dimensional models.
Proteins-structure Function and Bioinformatics, 2002
By Monte Carlo simulations, we explored the effect of single mutations on the thermodynamics and ... more By Monte Carlo simulations, we explored the effect of single mutations on the thermodynamics and kinetics of the folding of a two-dimensional, energetically frustrated, hydrophobic protein model. Φ-Value analysis, corroborated by simulations beginning from given sets of judiciously chosen initial contacts, suggests that the transition state of the model consists of a limited region of the native structure, that is, a folding nucleus. It seems that the most important contacts in the transition state (large and positive Φ) are not the ones with the highest contact order, because in this case the entropic cost of their formation would be too high, but exactly the ones that decrease the entropic cost of difficult contacts, reducing their effective contact order. Mutations of internal monomers involved in high-order contacts were actually the ones resulting in the fastest kinetics (and Φ < 0), indicating they tend to make low order, non-native contacts of low entropic cost that stabilize the unfolded state with respect to the transition state. Folding acceleration by other non-native interactions was also observed and a simple general mechanism is proposed according to which non-native contacts can act indirectly over the folding nucleus, “chelating” out potentially harmful contacts. The polymer graph of our model, which facilitates the visualization of effective contact orders, successfully suggests the relative kinetic importance of different contacts and is reasonably consistent with analogous graphs for the well characterized family of SH3 domains. Proteins 2002;49:167–180. © 2002 Wiley-Liss, Inc.
Transport Policy, 2007
One of the key questions in the evaluation of transport policies and investment decisions is the ... more One of the key questions in the evaluation of transport policies and investment decisions is the valuation of the time savings or losses arising from such decisions. This paper uses the stated preference method to determine the value of time in a given traffic context characterised by a road parallel network. The values obtained are higher than usual in Spanish project evaluation which, among other things, points out the need for specific studies of all transport projects whenever possible. Finally, two cases are described which illustrate the relevance of the value of time. The first evaluates time savings related to the pricing policies of a motorway competing with a trunk road. The second establishes the minimum amount of traffic that justifies the replacement of a single carriageway by a dual carriageway. r
Physical Review E, 2005
Conformational restrictions imposed by hydrogen bond formation during protein folding are investi... more Conformational restrictions imposed by hydrogen bond formation during protein folding are investigated by Monte Carlo simulations of a non-native-centric, two-dimensional, hydrophobic model in which the formation of favorable contacts is coupled to an effective reduction in lattice coordination. This scheme is intended to mimic the requirement that polar backbone groups of real proteins must form hydrogen bonds concomitantly to their burial inside the apolar protein core. In addition to the square lattice, with z = 3 conformations per monomer, we use extensions in which diagonal step vectors are allowed, resulting in z = 5 and z = 7. Thermodynamics are governed by the hydrophobic energy function, according to which hydrophobic monomers tend to make contacts unspecifically while the reverse is true for hydrophilic monomers, with the additional restriction that only contacts between monomers adopting one of z h Ͻ z local conformations contribute to the energy, where z h is the number of local conformations assumed to be compatible with hydrogen bond formation. The folding transition abruptness and van't Hoff-to-calorimetric-enthalpy ratio are found to increase dramatically by this simple and physically motivated mechanism. The observed increase in folding cooperativity is correlated to an increase in the convexity of the underlying microcanonical conformational entropy as a function of energy. Preliminary simulations in three dimensions, even though using a smaller relative reduction in lattice effective coordination z h / z =4/5, display a slight increase in cooperativity for a hydrophobic model of 40 monomers and a more pronounced increase in cooperativity for a native-centric Go-model with the same native conformation, suggesting that this purely entropic effect is not an artifact of dimensionality and is likely to be of fundamental importance in the theoretical understanding of folding cooperativity.
Proteins-structure Function and Bioinformatics, 2006
Monte Carlo simulations of a hydrophobic protein model of 40 monomers in the cubic lattice are us... more Monte Carlo simulations of a hydrophobic protein model of 40 monomers in the cubic lattice are used to explore the effect of energetic frustration and interaction heterogeneity on its folding pathway. The folding pathway is described by the dependence of relevant conformational averages on an appropriate reaction coordinate, pfold, defined as the probability for a given conformation to reach the native structure before unfolding. We compare the energetically frustrated and heterogeneous hydrophobic potential, according to which individual monomers have a higher or lower tendency to form contacts unspecifically depending on their hydrophobicities, to an unfrustrated homogeneous Go-type potential with uniformly attractive native interactions and neutral non-native interactions (called Go1 in this study), and to an unfrustrated heterogeneous potential with neutral non-native interactions and native interactions having the same energy as the hydrophobic potential (called Go2 in this study). Folding kinetics are slowed down dramatically when energetic frustration increases, as expected and previously observed in a two-dimensional model. Contrary to our previous results in two dimensions, however, it appears that the folding pathway and transition state ensemble can be significantly dependent on the energy function used to stabilize the native structure. The sequence of events along the reaction coordinate, or the order along this coordinate in which different regions of the native conformation become structured, turns out to be similar for the hydrophobic and Go2 potentials, but with analogous events tending to occur at lower pfold values in the first case. In particular, the transition state obtained from the ensemble around pfold = 0.5 is more structured for the hydrophobic potential. For Go1, not only the transition state ensemble but the order of events itself is modified, suggesting that interaction heterogeneity, in addition to energetic frustration, can have significant effects on the folding mechanism, most likely by modifying the probability of different contacts in the unfolded state, the starting point for the folding reaction. Although based on a simple model, these results provide interesting insight into how sequence-dependent switching between folding pathways might occur in real proteins.
Physical Review E, 2001
We show that a nonspecific hydrophobic energy function can produce proteinlike folding behavior o... more We show that a nonspecific hydrophobic energy function can produce proteinlike folding behavior of a three-dimensional protein model of 40 monomers in the cubic lattice when the native conformation is chosen judiciously. We confirm that monomer inside/outside segregation is a powerful criterion for the selection of appropriate structures, an idea that was recently proposed with basis on a general theoretical analysis and simulations of much simpler two-dimensional models.
Proteins-structure Function and Bioinformatics, 2002
By Monte Carlo simulations, we explored the effect of single mutations on the thermodynamics and ... more By Monte Carlo simulations, we explored the effect of single mutations on the thermodynamics and kinetics of the folding of a two-dimensional, energetically frustrated, hydrophobic protein model. Φ-Value analysis, corroborated by simulations beginning from given sets of judiciously chosen initial contacts, suggests that the transition state of the model consists of a limited region of the native structure, that is, a folding nucleus. It seems that the most important contacts in the transition state (large and positive Φ) are not the ones with the highest contact order, because in this case the entropic cost of their formation would be too high, but exactly the ones that decrease the entropic cost of difficult contacts, reducing their effective contact order. Mutations of internal monomers involved in high-order contacts were actually the ones resulting in the fastest kinetics (and Φ < 0), indicating they tend to make low order, non-native contacts of low entropic cost that stabilize the unfolded state with respect to the transition state. Folding acceleration by other non-native interactions was also observed and a simple general mechanism is proposed according to which non-native contacts can act indirectly over the folding nucleus, “chelating” out potentially harmful contacts. The polymer graph of our model, which facilitates the visualization of effective contact orders, successfully suggests the relative kinetic importance of different contacts and is reasonably consistent with analogous graphs for the well characterized family of SH3 domains. Proteins 2002;49:167–180. © 2002 Wiley-Liss, Inc.