It has been demonstrated earlier that the neural network based program AlphaFold2 can be used to ... more It has been demonstrated earlier that the neural network based program AlphaFold2 can be used to dock proteins given the two sequences separated by a gap as the input. The protocol presented here combines AlphaFold2 with the physics based docking program ClusPro. The monomers of the model generated by AlphaFold2 are separated, re-docked using ClusPro, and the resulting 10 models are refined by AlphaFold2. Finally, the five original AlphaFold2 models are added to the 10 AlphaFold2 refined ClusPro models, and the 15 models are ranked by their predicted aligned error (PAE) values obtained by AlphaFold2. The protocol is applied to two benchmark sets of complexes, the first based on the established protein-protein docking benchmark, and the second consisting of only structures released after May 2018, the cut-off date for training AlphaFold2. It is shown that the quality of the initial AlphaFold2 models improves with each additional step of the protocol. In particular, adding the AlphaFo...
Journal of The Franklin Institute-engineering and Applied Mathematics, Mar 1, 1998
Water serves as a critical solvent for a remarkable array of molecules; in particular it profound... more Water serves as a critical solvent for a remarkable array of molecules; in particular it profoundly influences the structure and activity of proteins, and their molecular interactions. Our ability to understand biological processes and to develop innovative applications for biotechnology depend in large part on understanding the biophysics of proteins in their solvated environment. The main difficulty in understanding solvation phenomena arises from the effects of electrostatics in complex biomolecular systems. In this paper we survey and critique the fundamental concepts and methodologies in evaluating electrostatic contributions to solvation.
American Journal of Physiology-Cell Physiology, 1991
Energy minimization is one of the main approaches to the computational determination of macromole... more Energy minimization is one of the main approaches to the computational determination of macromolecular structure. Due to the approximations in the empirical free-energy functions and due to the computational difficulties in locating their global minima, the problem is at present intractable when the only information available is the sequence of subunits forming the molecule. A less-demanding problem in terms of both physics and mathematics is constrained optimization, which uses additional but incomplete experimental information such as distances between certain atoms. This paper reviews methods for generating molecular structure using bond lengths and angles as variables and shows how the structure can be fully specified in terms of local geometry. The analysis permits precise statements to be made about the minimum set of distances that specify a unique structure without recourse to energy minimization. We then discuss the complementary situation, i.e., structure prediction with e...
An extended dynamic programming algorithm is presented that is applicable to the fragment assembl... more An extended dynamic programming algorithm is presented that is applicable to the fragment assembly phase of the site mappingfiagment assembly approach to peptide docking. After constructing a free energy map of the receptor using each of the amino acids in the peptides to be docked, we apply the algorithm to two systems: HIV-1 protease complexed with a synthetic hexameric inhibitor, and MHC HLA-A2 complexed with a nonameric peptide. The all atom root meano square deviation between the predicted and crystal structures was 1.7 and 2.0 A, respectively. While these results are reasonable considering the relatively coarse level of mapping, the more important result is that the structures are probably very close to the best obtainable by an exhaustive search through the entire data map, and yet are obtained with a reduction of 3-5 orders of magnitude in the number of computations. We also outline a prescription for an iterative procedure which finds the global minimum with increasing confidence.
The goal of our research is to discover small molecule lead structures for modulation of the prot... more The goal of our research is to discover small molecule lead structures for modulation of the protein-protein interaction between Kelch-like ECH-associated protein 1 (Keap1) and Nuclear factor eryth...
It has been demonstrated earlier that the neural network based program AlphaFold2 can be used to ... more It has been demonstrated earlier that the neural network based program AlphaFold2 can be used to dock proteins given the two sequences separated by a gap as the input. The protocol presented here combines AlphaFold2 with the physics based docking program ClusPro. The monomers of the model generated by AlphaFold2 are separated, re-docked using ClusPro, and the resulting 10 models are refined by AlphaFold2. Finally, the five original AlphaFold2 models are added to the 10 AlphaFold2 refined ClusPro models, and the 15 models are ranked by their predicted aligned error (PAE) values obtained by AlphaFold2. The protocol is applied to two benchmark sets of complexes, the first based on the established protein-protein docking benchmark, and the second consisting of only structures released after May 2018, the cut-off date for training AlphaFold2. It is shown that the quality of the initial AlphaFold2 models improves with each additional step of the protocol. In particular, adding the AlphaFo...
Journal of The Franklin Institute-engineering and Applied Mathematics, Mar 1, 1998
Water serves as a critical solvent for a remarkable array of molecules; in particular it profound... more Water serves as a critical solvent for a remarkable array of molecules; in particular it profoundly influences the structure and activity of proteins, and their molecular interactions. Our ability to understand biological processes and to develop innovative applications for biotechnology depend in large part on understanding the biophysics of proteins in their solvated environment. The main difficulty in understanding solvation phenomena arises from the effects of electrostatics in complex biomolecular systems. In this paper we survey and critique the fundamental concepts and methodologies in evaluating electrostatic contributions to solvation.
American Journal of Physiology-Cell Physiology, 1991
Energy minimization is one of the main approaches to the computational determination of macromole... more Energy minimization is one of the main approaches to the computational determination of macromolecular structure. Due to the approximations in the empirical free-energy functions and due to the computational difficulties in locating their global minima, the problem is at present intractable when the only information available is the sequence of subunits forming the molecule. A less-demanding problem in terms of both physics and mathematics is constrained optimization, which uses additional but incomplete experimental information such as distances between certain atoms. This paper reviews methods for generating molecular structure using bond lengths and angles as variables and shows how the structure can be fully specified in terms of local geometry. The analysis permits precise statements to be made about the minimum set of distances that specify a unique structure without recourse to energy minimization. We then discuss the complementary situation, i.e., structure prediction with e...
An extended dynamic programming algorithm is presented that is applicable to the fragment assembl... more An extended dynamic programming algorithm is presented that is applicable to the fragment assembly phase of the site mappingfiagment assembly approach to peptide docking. After constructing a free energy map of the receptor using each of the amino acids in the peptides to be docked, we apply the algorithm to two systems: HIV-1 protease complexed with a synthetic hexameric inhibitor, and MHC HLA-A2 complexed with a nonameric peptide. The all atom root meano square deviation between the predicted and crystal structures was 1.7 and 2.0 A, respectively. While these results are reasonable considering the relatively coarse level of mapping, the more important result is that the structures are probably very close to the best obtainable by an exhaustive search through the entire data map, and yet are obtained with a reduction of 3-5 orders of magnitude in the number of computations. We also outline a prescription for an iterative procedure which finds the global minimum with increasing confidence.
The goal of our research is to discover small molecule lead structures for modulation of the prot... more The goal of our research is to discover small molecule lead structures for modulation of the protein-protein interaction between Kelch-like ECH-associated protein 1 (Keap1) and Nuclear factor eryth...
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Papers by Sandor Vajda