Biomedical subjects

V S Pande

Publications and source records attributed to V S Pande.

11 recordsLinked to original sources

PubMed2001

Mathematical analysis of coupled parallel simulations.

A set of parallel replicas of a single simulation can be statistically coupled to closely approximate long trajectories. In many cases, this produces nearly linear speedup over a single simulation ( M times faster with M simulations), rendering previously intractable problems within reach of large computer clusters. Interestingly, by varying the coupling of the parallel simulations, it is possible in some systems to obtain greater than linear speedup. The methods are generalizable to any search algorithm with long residence times in intermediate states.

Journal Article↗

PubMed2000

Mechanical unfolding of a beta-hairpin using molecular dynamics.

Single-molecule mechanical unfolding experiments have the potential to provide insights into the details of protein folding pathways. To investigate the relationship between force-extension unfolding curves and microscopic events, we performed molecular dynamics simulations of the mechanical unfolding of the C-terminal hairpin of protein G. We have studied the dependence of the unfolding pathway on pulling speed, cantilever stiffness, and attachment points. Under conditions that generate low forces, the unfolding trajectory mimics the untethered, thermally accessible pathway previously proposed based on high-temperature studies. In this stepwise pathway, complete breakdown of backbone hydrogen bonds precedes dissociation of the hydrophobic cluster. Under more extreme conditions, the cluster and hydrogen bonds break simultaneously. Transitions between folding intermediates can be identified in our simulations as features of the calculated force-extension curves.

Biomechanical Phenomena↗

PubMed1999

Simulation of biomimetic recognition between polymers and surfaces.

Many biological processes, such as transmembrane signaling and pathogen-host interactions, are initiated by a protein recognizing a specific pattern of binding sites on part of a membrane or cell surface. By recognition, we imply that the polymer quickly finds and then adsorbs strongly on the pattern-matched region and not on others. The development of synthetic systems that can mimic such recognition between polymers and surfaces could have significant impact on advanced applications such as the development of sensors, molecular-scale separation processes, and synthetic viral inhibition agents. Attempting to affect recognition in synthetic systems by copying the detailed chemistries to which nature has been led over millenia of evolution does not seem practical for most applications. This leads us to the following question: Are there any universal strategies that can affect recognition between polymers and surfaces? Such generic strategies may be easier to implement in abiotic applications. We describe results that suggest that biomimetic recognition between synthetic polymers and surfaces is possible by exploiting certain generic strategies, and we elucidate the kinetic mechanisms by which this occurs. Our results suggest convenient model systems for experimental studies of dynamics in free energy landscapes characteristic of frustrated systems.

Algorithms↗

PubMed1999

Molecular dynamics simulations of unfolding and refolding of a beta-hairpin fragment of protein G.

We have studied the unfolding and refolding pathway of a beta-hairpin fragment of protein G by using molecular dynamics. Although this fragment is small, it possesses several of the qualities ascribed to small proteins: cooperatively formed beta-sheet secondary structure and a hydrophobic "core" of packed side chains. At high temperatures, we find that the beta-hairpin unfolds through a series of sudden, discrete conformational changes. These changes occur between states that are identified with the folded state, a pair of partially unfolded kinetic intermediates, and the unfolded state. To study refolding at low temperatures, we perform a series of short simulations starting from the transition states of the discrete transitions determined by the unfolding simulations.

Amino Acid Sequence↗

PubMed1999

Folding pathway of a lattice model for proteins.

The folding of a protein-like heteropolymer is studied by using direct simulation of a lattice model that folds rapidly to a well-defined "native" structure. The details of each molecular folding event depend on the random initial conformation as well as the random thermal fluctuations of the polymer. By analyzing the statistical properties of hundreds of folding events, a classical folding "pathway" for such a polymer is found that includes partially folded, on-pathway intermediates that are shown to be metastable equilibrium states of the polymer. These results are discussed in the context of the "classical" and "new" views of folding.

Models, Chemical↗

PubMed1998

Is the molten globule a third phase of proteins?

The equilibrium properties of proteins are studied by Monte Carlo simulation of two simplified models of protein-like heteropolymers. These models emphasize the polymeric entropy of the fluctuating polypeptide chain. Our calculations suggest a generic phase diagram that contains a thermodynamically distinct "molten globule" state in addition to a rigid native state and a nontrivial unfolded state. The roles of side-chain packing and loop entropy are discussed.

Chemical Phenomena↗

PubMed1998

Pathways for protein folding: is a new view needed?

Theoretical studies using simplified models of proteins have shed light on the general heteropolymeric aspects of the folding problem. Recent work has emphasized the statistical aspects of folding pathways. In particular, progress has been made in characterizing the ensemble of transition state conformations and elucidating the role of intermediates. These advances suggest a reconciliation between the new ensemble approaches and the classical view of a folding pathway.

Computer Simulation↗

PubMed1997

Statistical mechanics of simple models of protein folding and design.

It is now believed that the primary equilibrium aspects of simple models of protein folding are understood theoretically. However, current theories often resort to rather heavy mathematics to overcome some technical difficulties inherent in the problem or start from a phenomenological model. To this end, we take a new approach in this pedagogical review of the statistical mechanics of protein folding. The benefit of our approach is a drastic mathematical simplification of the theory, without resort to any new approximations or phenomenological prescriptions. Indeed, the results we obtain agree precisely with previous calculations. Because of this simplification, we are able to present here a thorough and self contained treatment of the problem. Topics discussed include the statistical mechanics of the random energy model (REM), tests of the validity of REM as a model for heteropolymer freezing, freezing transition of random sequences, phase diagram of designed ("minimally frustrated") sequences, and the degree to which errors in the interactions employed in simulations of either folding and design can still lead to correct folding behavior.

Biophysical Phenomena↗

PubMed1997

On the theory of folding kinetics for short proteins.

BACKGROUND: Recent data have suggested two principles that are central to the work we describe here. First, proteins are the result of evolutionary 'sequence selection' to optimize the energy of the native state. Second, the overlap with the native state is a qualitatively suitable reaction coordinate for modeling folding kinetics. The former principle is bolder and better established. RESULTS: Employing only these two principles, we have constructed a non-phenomenological, correlated energy landscape theory that predicts single barrier protein folding kinetics. Moreover, we are able to analytically describe the nature of the free energetic barrier between the denatured and native states of a protein and to detail the nature of folding kinetics for short proteins. Our model predicts Hammond behavior and also describes how mutations can lead to drastic differences in folding times. CONCLUSIONS: We find that folding and unfolding kinetics can be characterized by a single thermodynamic parameter and, moreover, that Monte Carlo simulation data on folding and unfolding rates with different temperatures and mutations collapse with this characterization. Our results also delineate a regime in which kinetics may proceed via a single unique nucleus.

Computer Simulation↗

PubMed1994

Nonrandomness in protein sequences: evidence for a physically driven stage of evolution?

The sequences, or primary structures, of existing biopolymers--in particular, proteins--are believed to be a product of evolution. Are the sequences random? If not, what is the character of this nonrandomness? To explore the statistics of protein sequences, we use the idea of mapping the sequence onto the trajectory of a random walk, originally proposed by Peng et al. [Peng, C.-K., Buldyrev, S. V., Goldberger, A. L., Havlin, S., Sciortino, F., Simons, M. & Stanley, H. E. (1992) Nature (London) 356, 168-170] in their analysis of DNA sequences. Using three different mappings, corresponding to three basic physical interactions between amino acids, we found pronounced deviations from pure randomness, and these deviations seem directed toward minimization of the energy of the three-dimensional structure. We consider this result as evidence for a physically driven stage of evolution.

Amino Acid Sequence↗

PubMed1994

Thermodynamic procedure to synthesize heteropolymers that can renature to recognize a given target molecule.

We suggest a procedure to synthesize polymers with characteristics similar to those observed in globular proteins: renaturability and the existence of an "active site" capable of specifically recognizing a given target molecule. This procedure is investigated by computer simulation, which finds a yield of up to 65%. We believe that, in principle, this scheme can be realized in vitro. The applicability of this approach as a model of prebiotic synthesis in vivo is also discussed.

Chemical Phenomena↗